Grapefruit-Drug Interactions Can Interactions With Drugs Be Avoided

The Journal of Clinical
Pharmacology
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Grapefruit-Drug Interactions: Can Interactions With Drugs Be Avoided?

S. U. Mertens-Talcott, I. Zadezensky, W. V. De Castro, H. Derendorf and V. Butterweck
J. Clin. Pharmacol. 2006; 46; 1390
DOI: 10.1177/0091270006294277
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DRUG INTERACTIONS
Grapefruit-Drug Interactions: Can

Interactions With Drugs Be Avoided?
S. U. Mertens-Talcott, I. Zadezensky, W. V. De Castro,
H. Derendorf, and V. Butterweck
Grapefruit is rich in flavonoids, which have been demon- and organic anion transporters have also been reported.
strated to have a preventive influence on many chronic This review is designed to provide a comprehensive sum-
diseases, such as cancer and cardiovascular disease. mary of underlying mechanisms of interaction and human
However, since the early 1990s, the potential health bene- clinical trials performed in the area of grapefruit drug
fits of grapefruit have been overshadowed by the possible interactions and to point out possible replacements for
risk of interactions between drugs and grapefruit and drugs with a high potential for interactions.
grapefruit juice. Several drugs interacting with grapefruit
are known in different drug classes, such as HMG-CoA
reductase inhibitors, calcium antagonists, and immunosu- Keywords: grapefruit; drug interactions; clinical
pressives. Currently known mechanisms of interaction relevance
include the inhibition of cytochrome P450 as a major Journal of Clinical Pharmacology, 2006;46:1390-1416
mechanism, but potential interactions with P-glycoprotein ©2006 the American College of Clinical Pharmacology
History of Grapefruit Drug Interactions investigating the interactions of grapefruit and dif-
ferent drugs. Grapefruit juice has been demonstrated
For approximately one and a half decades, a major to alter the pharmacokinetics of several drugs such
focal point in the area of food-drug interactions has as statins, calcium channel blockers, antibiotics, and
been placed on interactions of grapefruit with several others.2-9 Other fruits, vegetables, and dietary sup-
drugs such as lipid-lowering drugs and calcium chan- plements also have the potential to cause an adverse
nel blockers.1 An initial report regarding grapefruit interaction with conventional drugs.10
juice–drug interactions was published in 1991. These The reduction of the “first-pass” metabolism
interactions were discovered accidentally in a study through the inhibition of intestinal CYP3A4 seems
on ethanol drug interactions: grapefruit juice was to be the major mechanism in the induction of the
used to mask the taste of ethanol in this study. The grapefruit–drug interaction.11 Hydroxymethylglutaryl-
bioavailability of the drug felodipine was increased coenzyme A (HMG-CoA) reductase inhibitors and cal-
when subjects were consuming grapefruit juice (GFJ) cium channel antagonists are among the affected
concomitantly with felodipine. This increase was drugs.12 More recently, GFJ has also been found
associated with a lower dehydrofelodipine/felodip- to inhibit the intestinal P-glycoprotein-mediated
ine area under the curve (AUC) ratio, decreased dias- efflux transport of several drugs, increasing their
tolic blood pressure, and an increased heart rate.2 oral bioavailability.13-16 Other mechanisms of inter-
Since then, several studies have been conducted action (eg, altered activity of enzymes other than
CYP3A4) within the CYP450 family17-20 have been
assessed. Several in vitro studies have recently
From the Department of Pharmaceutics, Center for Food Drug Interaction demonstrated the potential influence of GFJ and
Research and Education, University of Florida, Gainesville. Submitted for other fruit juices on a number of organic anion-trans-
publication April 28, 2006; revised version accepted August 20, 2006.
Address for reprints: V. Butterweck, Department of Pharmaceutics, Center
porting polypeptides (OATPs) a group of influx
for Food Drug Interaction Research and Education, JHMHC, POB transporters.21,22
110494, Gainesville, FL 32610-0494; e-mail: [email protected]. Overall, several human clinical trials demonstrate
DOI: 10.1177/0091270006294277 that grapefruit juice has a potential to interact with
1390 • J Clin Pharmacol 2006;46:1390-1416

GRAPEFRUIT-DRUG INTERACTIONS
different oral medications when consumed in mod- Several previous reviews addressed interactions of
erate amounts such as 1 to 2 servings.23 Comprehen- grapefruit and drugs, discussing aspects of involved
sive studies are not available for many drugs. However, drugs and grapefruit components, drug safety, respon-
the concern—that the concomitant administration of sibilities to the public, and potential solutions.1,30-35
grapefruit products with certain drugs may cause This review is designed to give a comprehensive
toxic effects based on increased exposure—has led update on underlying mechanisms, conducted clini-
to the recommendation to avoid the concomitant cal trials, and potential replacements for drugs affected
consumption of grapefruit products with drugs of by the consumption of grapefruit.
concern. Some drugs such as cyclosporine, sirolimus,
simvastatin, lovastatin, and felodipine carry a warn- History of the Grapefruit
ing label regarding the possibility of an interac-
tion.24 For example, a brand-name cyclosporine-based Although the vast majority of Citrus varieties are
immunosuppressant drug carries a label stating, supposed to have originated in the tropical and sub-
“Grapefruit and GFJ affect metabolism, increasing troprical regions of Southeast Asia,36,37 the grape-
blood concentrations of cyclosporine, thus should fruit, which receives this denomination because the
be avoided,”24 and a certain nifedipine-based drug is fruits grow as clusters similar to grapes, is believed
labeled as follows: “Co-administration of nifedipine to have been generated as an accidental sprout on
with GFJ resulted in approximately a 2-fold increase the island of Barbados in the Caribbean, where it
in nifedipine AUC and Cmax with no change in half- was first described as the forbidden fruit of Barbados
life. The increased plasma concentrations are most in 1750 by Griffith Hughes.38 The first scientific
likely due to inhibition of CYP3A4 related first-pass description of grapefruit is attributed to the botanist
metabolism. Co-administration of nifedipine with James Macfadyen in 1837, who named the forbidden
GFJ is to be avoided.”25 In addition, interactions fruit Citrus paradisi Macf.38 Several studies strongly
with certain medications also have been shown for support that grapefruit originated from an acciden-
Seville orange juice, but Seville oranges are usually tal hybrid between pummelo (Citrus maxima) and
not processed to juice.26,27 sweet orange (Citrus sinensis), which is a hybrid
Comprehensive conclusions regarding the clinical between pummelo and mandarin.39 Currently, Florida
significance of the observed or predicted grapefruit- is the world’s largest producer of grapefruit, averag-
drug interactions are still limited; therefore, definitive ing 2 million tons a year, followed by the state of
recommendations regarding their concomitant admin- Texas.40
istration with GFJ are not available for most drugs in
question. Most studies investigated acute interactions,
and only a few trials assessed the influence of chronic POLYPHENOLIC COMPOUNDS IN
consumption of grapefruit juice on drug absorption GRAPEFRUIT AND CITRUS WITH
and metabolism. Moreover, the determination of the POTENTIAL DRUG INTERACTIONS
clinical relevance of observed interactions in human
intervention trials is impaired by interindividual vari- Overall, flavonoids and other polyphenolic com-
ability.11 On the other hand, it should be noted that pounds contained in grapefruit have been associated
many drugs that show an interaction with grapefruit with an influence in the prevention of many chronic
may be replaced by another drug within the same drug diseases, such as several types of cancer and cardio-
class without known potential for an interaction. vascular disease, which has been demonstrated in sev-
Moreover, the concentrations of polyphenolics with a eral cohort and case control studies.41-44 Specifically,
known potential for drug interactions vary within a orange juice, grapefruit juice, and naringin, a major
great range in different grapefruit juices, which in part grapefruit flavonoid, have been shown to have a ben-
may explain the great variability between different eficial effect on the blood lipid profile and antioxidant
grapefruit-drug interaction studies.28 capacity in rats.45,46 In a recent clinical consumption
The overall attention of scientists, patients, and trial with obese patients, it was demonstrated that
health care professionals currently is focused mainly the consumption of half of a grapefruit 3 times per
on interactions of drugs with grapefruit products. day before each meal was associated with significant
However, other fruits and vegetables and dietary weight loss over a period of 12 weeks compared to
supplements—mainly St. John’s wort but also green the control group, as well as a significant reduction
tea and ginseng—may be an additional potential in 2-hour postglucose insulin concentrations. In the
source for drug interactions, as recently reviewed.29 same study, the consumption of grapefruit juice and
DRUG INTERACTIONS 1391

MERTENS-TALCOTT ET AL
Figure 1. Chemical structure of polyphenolics in citrus: (A) bergamottin, (B) 6´7´-dihydroxybergamottin, (C) naringenin, (D) naringin,
and (E) furanocoumarins-dimer GF-I-1.
grapefruit extract capsules was associated with sig- effects of grapefruit in weight management.47 Many
nificant weight loss in those subjects with metabolic consumers have become more aware of the health
syndrome. These data may indicate the beneficial benefits of antioxidant, phytochemical-rich fruits,
1392 • J Clin Pharmacol 2006;46:1390-1416

vegetables, and products that contain these com- may primarily be responsible for the interactions of
pounds. In 1997, GFJ was purchased by 21% of all GFJ with drugs. Most clinical trials have been per-
households as a popular antioxidant breakfast juice formed using grapefruit juice, which may contain
predominantly preferred by the elderly.48 furanocoumarins at varying concentrations.28 A
Polyphenolics present the major group of citrus recent clinical trial using grapefruit juice with and
compounds interacting with drugs. Included are without furanocoumarins demonstrated that fura-
hydroxycinnamic acids; flavonoids, such as fla- nocoumarins were mainly responsible for the inves-
vanones, flavones, and flavonols; anthocyanins; and tigated interaction with felodipine in this study.59 In
coumarins (see Figure 1 and appendix).49 this review, the term grapefruit is used as a general
Interactions between furanocoumarins, bergamot- term to describe fresh grapefruit and also grapefruit
tin (BG), and 6´7´-dihydroxybergamottin (DHBG), as juice. Among citrus varieties overall, grapefruit, sour
well as dimers of furanocoumarins and many drugs, orange (Seville), and also limes seem to have a higher
have been demonstrated in many in vitro and in potential among citrus species to interact with drugs,
vivo studies. Furanocoumarins have been demon- whereas other citrus varieties, such as sweet orange,
strated to interact with susceptible drugs by different seem to have an overall low potential to interfere with
mechanisms: effects on the activity of the intestinal medications.57 However, in studies using juices
enzyme CYP3A4 and also the transporters P-gp and rather than single compounds, orange juice and apple
OATP have been demonstrated. However, the CYP3A4- juice have also been shown to interact with drugs
mediated interactions have been confirmed in numer- in a few studies. A recent study in rats demon-
ous in vitro as well as human clinical trials, whereas strated that orange juice and apple juice decreased
the transporter-mediated drug interactions lack thor- the oral exposure of fexofenadine, possibly through
ough investigation in human clinical trials. Overall, the inhibition of OATP.61 In HeLa cells, orange juice
single polyphenolic compounds from grapefruit mainly at 5% strength inhibited the uptake of fexofena-
have been investigated in the in vitro studies, whereas dine in a concentration-dependent manner by an
predominantly grapefruit juice has been administered array of human and rat OATPs,21 and in human
in human clinical trials. This makes a direct com- embryonic kidney cells, orange juice inhibited the
parison and an assessment of responsible single uptake of estrone-3-sulfate, probably mediated through
polyphenolic compounds for in vivo interactions OATP-B.22 However, overall, it can be concluded that
difficult. Overall, in the in vitro studies, polyphenolic orange juice does not have a significant potential in
compounds, including BG, DHBG, furanocoumarin drug interactions.
dimers, quercetin, and naringenin, have been demon-
strated to inhibit cytochrome P450 3A4.50-55 Paine POSSIBLE MECHANISMS OF INTERACTION
and coworkers56 assessed the kinetics of reversible and
mechanism-based inhibition of CYP3A4 by BG and A food-drug interaction may be defined as the alter-
DHBG with midazolam and testosterone as probes in ation of absorption, metabolism, or effect of a drug by a
human intestinal microsomes: an increasing number of food component. The underlying mechanisms can be
human intervention studies confirm the contribution of classified into the 2 broad categories: pharmacokinet-
BG and DHBG to drug interactions with GFJ.17,57-59 ics, including alterations in absorption, distribution,
Several citrus polyphenolics have been demonstrated metabolism, and excretion, and pharmacodynamics,
to be involved in transporter-mediated drug interac- describing alterations in the drug concentration-
tion. BG, DHBG, naringin, bergaptol, bergapten, tan- effect relationship.62 Citrus components more com-
geretin, and nobiletin have been found to inhibit the monly affect pharmacokinetics of drugs rather than
transport of P-gp or OATP-mediated drug transport pharmacodynamics, which may shift the effect of
in vitro.22,51,60 the drug outside of its therapeutic window, possibly
The clinical relevance of data obtained from stud- leading either to loss of effects or undesired side
ies with single compounds is questionable because effects or even toxicity.1 Initially, the liver was assumed
most studies were performed in the in vitro systems, to be the major site of grapefruit-drug interactions.
limiting the predictability of the effects in vivo. However, it has been shown that the interaction only
Moreover, concentrations used in some of the in occurs when drugs are administered orally, not intra-
vitro studies exceed those expected upon consump- venously, which indicates that the interaction may take
tion of moderate amounts of citrus products in vivo. place during the gastrointestinal absorption phase.63,64
Overall, in vitro studies with single compounds In the following sections, the major currently known
demonstrated that furanocoumarins and their dimers mechanism of action including the inhibition of

enteric CYP3A4 and the more recently described compounds and found that DHBG induced a substrate-
effects of grapefruit on the intestinal transporters P- independent reversible and mechanism-based inhi-
gp and OATP are described. bition on CYP3A4 in human intestinal microsomes.
In contrast, BG, being more lipophilic than DHBG,
Cytochrome P450 Family was a substrate-dependent reversible and substrate-
independent mechanism-based inhibitor. Similar
CYP enzymes are bound to membranes of the endo- trends were found with cDNA-expressed CYP3A4.
plasmatic reticulum and are predominantly expressed For BG, the inhibition for testosterone was more
in the liver, although they are also present in extra- potent than for midazolam, possibly due to the
hepatic tissues such as the gut mucosa. The cytochrome higher affinity of BG for the testosterone binding
P450 (CYP) enzyme family is the major catalyst of site. As mechanism-based inhibitors, BG and DHBG
phase I drug biotransformation reactions. CYP3A4 is are substrates for CYP3A4. In conclusion, both fura-
the most abundantly expressed isoform, where the nocoumarins inactivate CYP3A4 by the binding
high expression levels in the intestinal mucosa and of the furanoepoxide to the apoprotein.56 Overall,
the broad substrate specificity may contribute to the BG and DHBG are described as mechanism-based
high susceptibility of CYP3A4 for citrus-drug inter- inhibitors of CYP3A4 (reviewed in Zhou et al76). The
actions.65 Many drugs, for which interactions with recovery time of intestinal CYP3A4 was determined
citrus have been demonstrated, are metabolized by in a human intervention trial after the consumption
CYP3A4. Grapefruit juice can inhibit the activity of of regular-strength GFJ and a single dose of midazo-
intestinal CYP3A4, which can lead to an interaction lam at 2, 26, 50, and 74 hours after administering
with drugs during their first passage from the intestinal the juice. After 2, 26, 50, and 74 hours, the AUC
lumen into the systemic circulation.66 The alteration was 1.65-, 1.21-, 1.21-, and 1.06-fold increased in
of intestinal CYP3A4 by GFJ includes reversible and comparison to the control, respectively. A recovery
mechanism-based inhibition as well as destruction half-life of 23 hours was estimated. These results
of the CYP3A4 protein,23,67 where mRNA levels remain imply that a single dose of GFJ may be able to reduce
unaltered, indicating an accelerated degradation after the intestinal presystemic metabolism of orally admin-
mechanism-based inhibition.68 Moderate consump- istered midazolam, with a recovery time of 74 hours.
tion did not appear to inhibit hepatic CYP3A4 activity.56 These results are consistent with a mechanism-based
Several drug classes, such as dihydropyridine cal- inhibition.18 Although DHBG was shown to be more
cium antagonists and HMG-CoA reductase inhibitors, potent than BG, coumarin dimers seem to be more
have been shown to be affected by grapefruit-induced effective than monomers in the inhibition of CYP3A4.55
inhibition of CYP3A4. Grapefruit juice increased the In summary, the presented in vitro studies con-
AUC and maximal plasma concentration (Cmax) for firm the inhibitory effects of grapefruit compounds
this class of calcium antagonists within a moder- on CYP enzymes, with major effects on CYP3A4,
ate range in a single-dose study design (reviewed involving both mechanism-based and reversible inhi-
in Harris et al65). Double-strength GFJ moderately bition. Human intervention trials revealed a great
increased the AUC of the HMG-CoA reductase interindividual variability, where subjects with the
inhibitors atorvastatin69 and simvastatin.70 This group highest concentrations of CYP3A4 showed the largest
also demonstrated that 1 glass of GFJ caused an increase reduction. Overall, GFJ does not seem to interact with
in plasma triazolam concentrations.71 In a 72-hour intravenously administered drugs. The extent of the
study, GFJ increased the AUC of simvastatin 3.6-fold grapefruit-drug interaction in the case of CYP3A4
and simvastatin acid 3.3-fold. The Cmax of simvas- seems to depend on individual intestinal enzyme
tatin and simvastatin acid was increased 3.9-fold activity. Subjects with a high activity of CYP3A4 appear
and 4.3-fold, respectively, when the GFJ was admin- to have a higher inhibition by GFJ than subjects with
istered for 3 days and simvastatin on the third day.72 a low initial CYP activity. Consequently, the con-
In addition to CYP3A4, other isoforms of the CYP comitant administration of GFJ with a susceptible
family—CYP2C9, CYP2C19, and CYP2D6—were drug may cause higher AUC in subjects with a high
shown to be affected by citrus compounds,73-75 but intestinal CYP3A4 activity, but unexpectedly, these
the inhibition of CYP enzymes other than CYP3A4 subjects tend to have a low AUC after intake of a
does not appear to be of great magnitude and is standard dose of drugs without the administration of
likely to be of a low clinical significance.65 GFJ.66,77 More studies will have to be performed
Paine and coworkers56 investigated the reversible before sound recommendations for the concomitant
and mechanism-based inhibition kinetics for grapefruit intake of citrus with certain drugs can be given.
1394 • J Clin Pharmacol 2006;46:1390-1416

P-Glycoprotein did not inhibit P-gp in vitro. These data imply that
the inhibition of P-gp activity by other compounds
One of the most studied drug transporters is P- in GFJ may be responsible for the increased bioavail-
glycoprotein (P-gp). P-glycoprotein is a 170-kDa plasma ability of cyclosporine, but cyclosporine also is a
glycoprotein of the family of adenosine triphosphate substrate for CYP3A4, which may have signifi-
(ATP)–binding cassette transporters, which is encoded cantly contributed to the increased bioavailability of
by the multidrug resistance MDR 1 gene.78,79 P-glyco- cyclosporine in this study. In a randomized 3-way
protein is expressed constitutively at high levels on crossover intervention study in which healthy vol-
the apical surface of the small intestine, liver, pan- unteers were administered felodipine as a probe
creas, kidney, colon, adrenal glands, and at the blood- with Seville orange juice, diluted GFJ (normalized to
brain barrier and blood–cerebrospinal fluid barriers.79-81 an equivalent total concentration of BG and DHBG),
Wacher and coworkers82 reported striking overlaps and sweet orange juice, the AUC of felodipine was
of substrates and inhibitors between CYP3A4 and increased by Seville orange juice and GFJ. Although
P-gp. Therefore, the inhibition of P-gp may also play Seville orange juice and GFJ probably interact with
a role in the effects of GFJ. felodipine through the inactivation of intestinal
Initial studies indicated that GFJ had no influence CYP3A4, there was no apparent interaction between
on the activity of P-gp: it was found that 8 oz of GFJ Seville orange juice and cyclosporine, which indi-
(3 times per day for 6 days) did not alter P-gp con- cated that grapefruit may cause interactions also
centrations in healthy volunteers.68 These findings through the inhibition of intestinal glycoprotein.84
were confirmed in an in vitro study in Caco-2 colon Conversely, the pharmacokinetics of known P-gp
carcinoma cells, where compounds from grapefruit substrates were not altered by GFJ in several clinical
were not found to modulate P-gp.51 In 1999, it was studies, which were designed to investigate the effect
reported that GFJ increased P-gp-mediated transport of GFJ on the bioavailability of digoxin, amlodipine,
in MDCK-MDR1 cells.83 Controversially, in later and indinavir26,91,92—potentially due to other unknown
findings, these results were attributed to an equipment- mechanisms and factors, such as strength of the
generated artifact by the authors.84 Takanaga and administered juices and length of consumption rele-
coworkers85 were the first to demonstrate the inhibi- vant for the interactions.93
tion of P-gp by GFJ in Caco-2 cells with vinblastine Overall, grapefruit and other citrus may interact
as a probe. Because vinblastine also is a substrate with several drugs through the combined inhibition
of CYP3A4, the conclusion regarding the inhibition of CYP3A4 with other mechanisms. The magnitude
of P-gp is limited. In a study investigating GFJ and of interactions may strongly depend on variations
phenolic compounds from oranges, such as tan- in the polyphenolic profile of the GFJs and study
geretin, nobiletin, and heptamethoxyflavone, which design.94,95 The clinical significance of P-gp-related
have been demonstrated not to alter CYP3A4 activ- interactions between drugs and GFJ will have to be
ity, it was shown that the net influx of vincristine clarified in further clinical studies.
into human myelogenous leukemia cells was increased
conclusively through the inhibition of P-gp.86 Further Organic Anion-Transporting Polypeptides
in vitro studies with different probes (talinolol,
digoxin, vinblastine) corroborate the findings that The family of OATPs consists of membrane carriers
GFJ inhibits the efflux of P-gp substrates.87-89 In addi- that mediate the transport of anionic molecules. More
tion to GFJ, orange juice and pummelo juice seem recently, the transport of nonanionic molecules has
to inhibit the activity of P-gp in vitro.89 Overall, been observed. Organic anion-transporting polypep-
flavones from orange juice have been shown to be tides can be found in the small intestine on luminal
more potent than compounds from grapefruit in the membranes of enterocytes and in the liver as media-
inhibition of P-gp.85 tors of drug uptake.96,97 OATP-A is predominantly
Few human clinical trials confirmed the possibility located in the brain, and OATP-B has been found on
of P-gp being involved in GFJ-drug interactions. A the membranes of intestinal epithelial cells.98,99 The
clinical intervention study conducted by Edwards and inhibition of drug uptake mediated by OATP may
coworkers90 indicated that GFJ may interact with P-gp alter the plasma concentration of drugs serving as
activity. In this study, AUC and peak concentration of OATP substrates.
cyclosporine were increased by GFJ. Seville orange Grapefruit juice and orange juice have been found to
juice did not have an influence on cyclosporine, but it reduce the uptake of fexofenadine and celiprolol, both
reduced enterocyte concentrations of CYP3A4. DHBG substrates for P-gp and OATP, but not CYP3A4.21,100-103

In the observed interaction, the bioavailability was In summary, OATPs appear to play an important
decreased—if P-gp had played a major role, the role in the influx for a number of drugs into entero-
bioavailability would have been increased instead. cytes and hepatocytes. The inhibition of OATP activ-
This observation led to the conclusion that a mech- ity has been demonstrated for orange and GFJ in the in
anism other than P-gp was involved. Several in vitro vitro experiments. The clinical relevance of this mech-
studies were designed to verify this observation, but anism remains to be investigated in further human
only few clinical trials have been performed to estab- intervention trials. The OATP-mediated GFJ-drug
lish the clinical significance of this mechanism. interactions may be of clinical relevance for drugs
Grapefruit juice and orange juice were found to such as itraconazole, fexofenadine, and talinolol.
decrease OATP-A-mediated fexofenadine uptake into
HeLa cells, and apparently, this inhibition of OATP-
A was more potent than the inhibition of P-gp. In CLASSES OF DRUGS INTERACTING
a corresponding human trial, the same authors WITH GRAPEFRUIT JUICE
determined that GFJ and orange juice decreased the
bioavailability of fexofenadine in healthy volunteers.21 Below, major drug classes for which grapefruit inter-
The authors discussed that the apparent decreased actions have been reported are comprehensively
bioavailability of fexofenadine in humans may have described and summarized. Previously, several clin-
been caused indirectly by an increased drug intake ical trials and underlying mechanisms on grapefruit-
when the drug was administered with water, due to drug interactions have been summarized, in which
the lower osmolarity of water. Therefore, a nonpolar drugs were classified into 3 groups (increase, decrease,
fraction of GFJ was tested in a clinical trial. This or no change in Cmax and AUC, respectively).105 It is
nonpolar fraction also significantly reduced the difficult to predict the clinical significance of phar-
bioavailability of fexofenadine, confirming the ini- macokinetic drug interactions, specifically for drugs
tial hypothesis. In 2 corresponding clinical inter- where side effects cannot be quantified. A recent
vention trials, the oral pharmacokinetics of 50 mg effort in the United States involving the Food and
talinolol were determined acute and after 6 days Drug Administration (FDA) and the Pharmaceutical
of repeated grapefruit juice ingestion (900 mL/d) Research and Manufacturers of America (PhRMA)
in 24 healthy volunteers. Results demonstrated has the goal to establish some general guidelines to
that the acute and chronic consumption of grape- help drug companies, prescribers, and patients inter-
fruit juice decreased the talinolol area under the pret the clinical significance of drug interactions.106
serum concentration-time curve (AUC), peak serum These guidelines are based on clinical experience
drug concentration (Cmax), and urinary excretion with several well-defined drug interactions, mainly
values by approximately 45% to 65% compared to including the inhibition of CYP3A4. For this inter-
water. However, renal clearance, elimination half- action mechanism, benzodiazepine midazolam was
life, or time to reach Cmax (tmax); MDR1 messenger shown to be a reproducible probe allowing quantita-
ribonucleic acid; and P-glycoprotein levels in duo- tive determination of the interaction potential of an
denal biopsy specimens were not affected by the enzyme inhibitor. For midazolam, the extent of inter-
grapefruit juice. Conclusively, grapefruit juice seemed action can be measured in the form of an increase in
to inhibit an intestinal uptake process compared to the AUC. Recently, it was suggested that less than 2-
P-glycoprotein, where intestinal P-glycoprotein expres- fold changes of midazolam AUC should be classified
sion was not altered.104 as “weak,” which was observed after midazolam coad-
Grapefruit juice, orange juice, BG, DHBG, quercetin, ministration with ranitidine, low volumes of GFJ,
naringin, naringenin, and tangeretin significantly roxithromycin, fentanyl, or azithromycin.106 AUC
inhibited OATP-B-mediated drug transport in vitro.22 changes ranging from 2- to 5-fold were classified as
In a study with rats, orange juice decreased the oral “moderate,” which occurs after midazolam coad-
bioavailability of fexofenadine to a lesser extent than ministration with erythromycin, diltiazem, flucona-
that observed in humans.61 The clinical relevance of zole, verapamil, large volumes of GFJ, and cimetidine.
this study does not appear to be high because fex- A strong interaction was marked by changes exceed-
ofenadine mainly is a substrate for OATP-A, which ing a 5-fold increase in midazolam AUC. Examples
in humans predominantly occurs in the brain, whereas include ketoconazole, itraconazole, and mibefradil.
OATP-B occurs in the intestines. In general, it should According to the current knowledge, strong drug inter-
be considered that genetic differences between species actions are considered clinically significant. Some
may contribute to differences in the susceptibility to drugs for which strong interactions have been shown
grapefruit-induced inhibition involving OATP. are carrying a warning label.
1396 • J Clin Pharmacol 2006;46:1390-1416

Where applicable, the clinical relevance of GFJ Antimalaria Drugs

interactions described in this review was assessed
according to the PhRMA classification.106 Below, cur- Grapefruit juice was found to increase the exposure
rently available scientific reports of human clinical of artemether119,120 and halofantrine.121 However, brady-
trials are summarized. In vitro studies or studies in cardia or changes in the QTc interval were not
animal models are listed where no human clinical reported for artemether when administered with GFJ.
data are available. An overview is given in the appen- No changes in pharmacokinetic parameters were
dix. A detailed overview and scientific summaries of observed when quinidine74,122 or quinine123 was coad-
the presented human clinical trials can be found on ministered with GFJ. However, quinidine was reported
the Web pages of the Center for Food Drug Interaction to have a QTc interval prolongation at 1 hour after
at the University of Florida (www.druginteraction- drug administration. According to the classification
center.org). Several nonscientific online databases of Bjornsson et al,106 the interactions of quinidine and
also provide information regarding grapefruit-drug quinine would be considered weak and unlikely to be
interactions. However, close attention should be paid clinically relevant, but the observed interaction with
to the source of reports and the scientific basis of halofantrine can be considered clinically relevant.
the presentation because much anecdotal, sensa-
tionalized, and nonscientific information may be Antiparasitic Drugs
presented.
A moderate and weak interaction is reported for
albendazole124 and praziquantel,125 respectively.
Antiallergics
Therefore, a concomitant consumption should only
be considered after a cautious risk and benefit assess-
Interaction studies are reported for the antiallergic
ment. An interaction of GFJ with praziquantel seems
drugs terfenadine,107-110 desloratadine,111 and fexofe-
unlikely to be clinically relevant, but a moderate
nadine.111 Concomitantly consumed GFJ did not alter
interaction was observed for albendazole.
the mean exposure for desloratadine, whereas for
fexofenadine, it was decreased. Three studies showed
increased exposure to terfenadine coadministered Sedative-Hypnotics
with GFJ.107-109 Overall, the effects of GFJ on this drug
class do not appear to be of high clinical relevance. No changes in pharmacokinetic parameters were
observed when alprazolam was administered con-
comitantly with GFJ126 in a single-dose experiment.
Antibiotics With midazolam,7,18,127,128 triazolam,71,128-131 and
quazepam,130 minor exposure increases were observed
Interaction studies were performed with clar- when administered concomitantly with GFJ. In a recent
ithromycin,112 erythromycin,113 and telithromycin.114 clinical trial with triazolam, the acute and extended
Overall, the clinical relevance of the reported inter- exposure to GFJ produced a significant inhibition of
actions with antibiotics appears to be low. enteric, but not hepatic, CYP3A4 and also caused
significant pharmacodynamic effects.131 A clinically
Anticoagulants relevant interaction has also been observed for bus-
pirone132 and diazepam.133 More human intervention
Inconsistent data were derived from studies performed trials will have to be conducted to investigate the
with coumarins. The percentage of 7-hydroxycoumarin extent of interactions for this drug class.
excreted in urine was found to be decreased,115 but
in a second study, the appearance of the metabolite Calcium Channel Blockers
was delayed, whereas the recovery in urine was
unchanged.116 The delay in appearance of the metabo- Amlodipine,91,134 diltiazem,135,136 nimodipine,137
lite was confirmed in a third study.117 No interactions nifedipine,2,138,139 pranidipine,140 and verapamil141-143
with warfarin have been confirmed.118 Currently, no were shown to interact weakly with GFJ. However,
clinically relevant interactions have been confirmed only for amlodipine, diltiazem, nimodipine, and
for this drug class. More extensive clinical studies verapamil were no changes reported in pharmaco-
are necessary to assess the overall effect of GFJ on dynamic parameters (heart rate and blood pressure).
this drug class. No pharmacodynamic alterations were reported for

nifedipine and GFJ. Felodipine,17,58,63,68,84,91,141-150 Antitumor Drugs

nicardipine,151 nisoldipine,152,153 nitrendipine,3 and
manidipine154 moderately interacted with GFJ. Changes Few studies have been performed with human subjects
in pharmacodynamic parameters were reported after for this drug class. The mean AUC of etoposide was
GFJ was administered with felodipine. Overall, prod- increased when administered concomitantly with
ucts containing felodipine, nicardipine, nisoldipine, GFJ.178 However, the report does not state the statis-
and nitrendipine should only be consumed with GFJ tical significance of the reported data. To develop
after a cautious risk and benefit assessment. recommendations for this drug class, further research
will have to be conducted. Currently, the clinical sig-
HIV Protease Inhibitors nificance of interactions with GFJ appears to be low.
Amprenavir155 and indinavir26,156 did not induce Over-the-Counter Drugs

changes in pharmacokinetic parameters when admin-
istered concomitantly with GFJ. The AUC of saquinavir Contradicting results were reported when caffeine
was increased by GFJ.9,157 However, overall, the was administered with GFJ. Whereas no changes in
reported interactions can be considered weak and AUC, blood pressure, and heart rate were reported
are unlikely to be clinically relevant. by Maish and coworkers,179 a second study found
increased AUC and half-life, without an assessment
HMG-CoA Reductase Inhibitors of pharmacodynamic parameters.180 Overall, no clin-
ically significant interactions of an over-the-counter
Increased exposures were reported for atorvas- drug with GFJ have been reported.
tatin,69,158,159 lovastatin,160,161 and simvastatin72,132,162 but
not for pravastatin69,158 and pitavastatin.159 Atorvastatin Beta-Blockers
exhibited a moderate interaction with GFJ regarding
the overall exposure. Lovastatin and simvastatin exhib- AUC and Cmax of celiprolol decreased by 95%, when
ited a strong interaction. Pravastatin or pitavastatin administered concomitantly with GFJ,100 but heart
could be chosen as an alternative drug if clinically rate and blood pressure remained unchanged. It is
recommendable and if patients want to ensure a lack conclusive that observed interactions are clinically
of interaction. Overall, the changes in pharmacoki- relevant. The plasma concentrations of acebutolol181
netics (AUC) of statins by far exceeded the extent of were slightly decreased by grapefruit juice. Further
pharmacodynamic changes. studies in humans will have to be conducted to
derive reliable conclusions. Currently, clinically sig-
Hormones nificant interactions appear to be unlikely.
Grapefruit juice did not affect 17-beta estradiol163 or Antiarrhythmics

prednisone164 pharmacokinetics. AUCs were weakly
elevated for ethinylestradiol165 and methylpred- Coadministration of amiodarone182 with regular-
nisolone.166 A decreased morning cortisol plasma strength GFJ resulted in a significant but weak
concentration was found after methylprednisolone increase in AUC and Cmax, but a decrease in the alter-
administration with GFJ. The absorption of levothy- ation on the PR and QTc interval was observed.
roxine was mildly decreased after repeated consump- These data imply that not only pharmacokinetic
tion of grapefruit juice, but here the authors conclude data should be considered when determining the
a low clinical relevance.167 Anecdotal reports that extent of the significance of a given GFJ-drug inter-
grapefruit juice may cause contraceptives to lose their action. Overall, the changes in pharmacodynamic
effect could not be confirmed by scientific studies. parameters should be taken into account when pre-
scribing this drug to patients who wish to consume
Immunosuppressants GFJ.
Eleven out of a total of 13 studies reported increased Other Drugs

cyclosporine exposure.64,90,168-176 Conversely, 2 stud-
ies reported no GFJ-induced change in AUC.164,177 Grapefruit juice has shown to increase the exposure
Overall, the clinical significance of interactions is of carbamazepine,183 cisapride,77,184-186 fluvoxamine,187
assumed to be low. losartan,188 methadone,189 scopolamine,190 sertraline,191
1398 • J Clin Pharmacol 2006;46:1390-1416

and repaglinide.192 However, only the interaction of 1. For patients taking unusually high doses of a sus-
GFJ and carbamazepine and cisapride appears to be ceptible drug who then consume GFJ for the first
clinically relevant. No alteration in exposure was time, GFJ may lead to a sudden decrease of intesti-
observed for clozapine,193,194 theophylline195 and nal CYP3A4 activity.
haloperidol,196 omeprazole,197 and phenytoin.198 Con- 2. In patients with severe liver disease, the exposure to
tradicting results were reported for itraconazole,199-201 the drug would be expected to be higher, with the
digoxin,92,202 and sildenafil.203,204 Overall, the clinical intestines being the major site of metabolism. Also
in these patients, a sudden decrease in CYP activity
relevance for this drug class appears to be minor.
in the intestines may lead to an increase of drug
concentration.
CONCLUSIONS 3. Patients susceptible to toxic effects from drugs are
likely to exhibit a drug toxicity when the bioavail-
Grapefruit juice has been shown to interact with ability is increased.11
several orally administered medications. In most cases,
the expected interactions will be minor and of little
clinical relevance. However, the overall observation FUTURE DIRECTIVES
that a single serving of GFJ can induce a long-lasting
increase in oral bioavailability of some drugs, which Overall, patients treated with drugs that have shown
may lead to a potential drug toxicity, does call for a significant potential for grapefruit-drug interaction
caution. For those patients who wish to consume need to the counseled regarding a concomitant use.
GFJ while taking a certain medication, potential Care must be taken to avoid careless prescription of
alternatives may be available for several of the drugs. susceptible drugs. A potential change to an alterna-
Conceptually, drugs with a strong interaction could tive drug without known interactions may be con-
be substituted by drugs within the same class that sidered. However, overcautious overreaction leading
exhibit a weak or no interaction. Where toxicity can to complete avoidance of citrus products seem
be expected, GFJ should be avoided during the period unreasonable, especially because these contain sig-
of drug treatment. In addition, the replacement with nificant amounts of antioxidant phytochemicals
noninteracting drugs is limited by their therapeutic with significant health benefits.
interchangeability and is dependent on a physician’s Further research is needed extending across more
recommendation and safety assessment. In this con- drugs for grapefruit, citrus fruits other than grape-
text, it should be considered that for patients who fruit, and other food products in general. Further
regularly consumed GFJ before the dose of their med- clinical research will have to be conducted to con-
ication was adjusted and continue with a constant clusively determine the mechanisms and clinical
consumption of GFJ during their medication, a poten- relevance of these interactions.
tial toxicity appears relatively unlikely.11
There are situations when toxicity is more likely Financial disclosure: This research was partially supported by
to occur: a grant from the US Department of Agriculture.

APPENDIX
1400
Antiallergics
Moderate Interaction (AUC Increase >2- < 5-fold)
Grapefruit Juice Parameters Pharmacokinetics
Drug Type Amount Dosing AUC Cmax t1/2 Other Pharmacodynamics Reference
Terfenadine DS 240 mL t = 0 or t + 2 Concentrations not SS increase in QTc interval 8

quantifiable in GFJ group was SS
RS/DS 250 mL — — QTc interval 109
No or Weak Interaction (AUC Increase ≤ 2-fold)
Desloratadine DS 240 mL tid — ECG 111

Fexofenadine DS 240 mL tid — Differences in ECG 111
parameters were
not significant
DS 240 mL bid — Ke QTc interval , ECG 108
FS 300 mL t-30 — — QTc 107
Antibiotics
Calithromycin FS 240 mL t0 and t-24 — NA 112

Erythromycin DS 300 mL t-30 — NA 113
Telithromycin RS 240 mL — — No serious AE reported 114
Anticoagulants
Warfarin FS 237 mL tid (for — — — — Prothrombine time , 118

1 week) International
normalized ratio
Antimalaria Drugs
Strong Interaction (AUC Increase ≥ 5-fold)
Halofantrine RS 250 mL @8:00 AM — QTc prolongation 121

and t-72,
t-48, t-24, t-12
Artemether DS 350 mL concomitant — No sign of bradycardia, 119

QTc interval
DS 350 mL concomitant — NA 120
Qunidine RS 250 mL bid — Median Median Clren NA 74

Median Cloral
RS 237 mL @8:00 AM — Change in QTc interval 122
SS only 1 hour
after administration
Quinine RS/HS 200 mL For 5 days bid — NA 123
Antiparasitic Drugs
Albendazole DS 250 mL — — NA 124
No or Weak Interaction (AUC Increase ? 2-fold)
Praziquamtele CS 250 mL — — NA 125
1401
(continued)
APPENDIX (continued)
Sedative Hypnotics
1402
Strong Interaction (AUC Increase ≥ 5-fold)
Buspirone DS 200 mL bid for 2 days — SOE PSF 132

and t + 1,
t + 1.5 h
Diazepam RS 250 mL 5 mg diazepam — — 133
Midazolam 1–RS 1–300 mL 1 1- — — — 1- DST 128

2–RS 2–300 mL 2– with 750 mg 2– 2– — — FFT
erythromycin
2- NA
RS 200 mL t-60, t-15 po – — — po– PSF 7
(po, iv) F(%)
iv– — — iv–
RS 200 mL t-60, t-15 (NS) — NA 127
RS 296 mL — CL NA 18
Sedative Hypnotics
Triazolam 1–RS 1–200 mL 1–qd 1– 1– 1– — 1 & 2- 71

2–DS 2–200 mL 2–qd 2– 2– 2– — PSF
3–DS 3–200 mL 3–tid 3– 3– 3– — SOE
3–PSF
DW
— 300 mL — — — — — PSF (slight but 128
significant)
RS 250 mL — — DW 129
PSF
RS 250 mL t = 0, t = 4, — DSST Drowsiness 130
t = 12 Mental slowness
RS 300 mL OD acute acute acute — acute: EEG β amplitude 131
extended extended extended DSST extended: EEG
b amplitude DSST
Alprazolam 1–RS 1–200 mL 1–tid –8 days + 1– 1– 1– — 1- PSF 126

2 days
2–RS 2–200 mL 2-alprazolam 2– 2– — 2– — — TS with GFJ treatment at
predosing 2-10 nonsmokers: time points 1 h and 2 h
weeks, GFJ tid
for 7 days
Smokers: 2- PSF
Quazepam RS 250 mL t = 0, t = 4, (NS) — DSST 130

t = 12
Drowsiness
Calcium Channel Blocker
Felodipine 1–RS 1–250 mL 1– — 1– 1– 1– 1– — 1–NA 148

2–BG 2–2mg 2– — 2– — 2– 2– — 2– — 2–NA
3–BG 3–6mg 3– — 3– — 3– 3– — 3– — 3–NA
4–BG 4–12mg 4– — 4– 4– 4– — 4– — 4–NA
RS 200 mL — — HR , BP 63
RS 250 mL — — NA 146
RS 237 mL tid — — NA 68
FF 200 mL — — NA 145
RS 250 mL — — SD: HR , BP 147
SS (rename): HR , BP
1–SF 1–240 mL 1– — 1– — 1– — 1– — 1– — 1–NA 56
2–PF 2–9g 2– — 2– — 2– — 2– — 2– — 2–NA
3–whole 3–250 mL 3– — 3– 3- 3– 3– — 3–NA
GFJ
DG (diluted 240 mL — — NA 84
GFJ 1.3:1)
RS 200 mL qd 14 days day 1: day 1: day 1: day 1: — HR 144
day 14: day 14: day 14: day 14:—
RS 240 mL — — — NA 17
RS 200 mL — — SHR , DBP 149
DS 250 mL — — — BP , HR 2
RS 250 mL — — NA 150
(continued)
1403
Calcium Channel Blocker
1404
Nitrendipine RFG 150 mL — — HR , BP 3

Nisoldipine RS 250 mL — — — NA 152
RS 200 mL tid for 7 days + (@ 0,14,38,72h) (@0,14 h) — BP 153
t + 0, t + 14, t + 38,
t + 72, t + 96 h
Nicardipine RS 300 mL — — — CL ABP ,HR (1 & 2 h), ECG 151
Manidipine RS 250 mL @0h — HR BP mild to 154
moderate AE reported
Pranidipine RS 250 mL — — BP , HR 140

Nimodipine RS 250 mL — — Max HR , BP 137
Nefedipine RS 200 mL @0, 2, 4, 8, 12 h — NA 139
after drug admin
DS 200 mL — — NA 138
2
RS 250 mL — — NA
Amlodipine FJ 250 mL — — BP , HR 91
RS 240 mL 200 mL for 8 days — BP , HR 134
with drug after drug admin
Diltiazem RS 250 mL — (NS) — NA 135

FSJ 200 mL @ 0, 2, 4, 8, 12 h — ABP 136
after drug admin
HR
PR interval
Verapamil RS 250 mL 4 times @ 0, 3, AUCss Cmaxss — F NA 141
8, 12 h (NSR) (NSR) (NSR)
RS 200 mL bid (5 days Cmin BP 142
pretreatment)
HR
PR interval
RS 200 mL — — — NA 143
HIV Protease Inhibitors
Amprenavir RS 200 mL — * ** — — No adverse events reported 143

26
Indinavir RS 237 mL — — NA
DS 180 mL — — — NA 156
9
Saquinavir RS 200 mL t-45 t-15 F(%) NA
RS 250 mL (n = 1) (NSR) — — — NA 157
Hormones
17-beta estradiol RS 200 mL — — — No adverse events reported 164

Ethinyl estradiol RS 2 × 10 mL — — — NA 165
Prednisone RS 150 mL Q3h over 30 h — — NA 164
Methylprednisolone DS 200 mL tid for 2 days Morning plasma 166
cortidsol conc $
Levothyroxine RS 200 mL tid for 2 days — — NA 167
Antitumor Drugs
Etoposide RS 100 mL — (NSR) — — — NA 178
Over-the-Counter Drugs
Caffeine RS 200 mL — — — Ke BP , HR 179

RS 300 mL t0 and q6h — Cloral NA 180
(continued)
1405
1406
Beta-Blocker
Strong Interaction (AUC Increase ≤ 5-fold)
Celiprolol RS 200 mL tid for 2 days — Clrenal BP 100

HR
Weak interaction <2 fold
Acebutolol RS 200 mL tid for 2 days — BP HR {Lilja, 2005
#128}
Antiarrhythmics
Amiodarone RS 300 mL @ 0, 3, & 9 h — RR intervals and QRS 182

after drug duration were not
intake statistically altered;
decrease in alterations
on PR and QTc
Immunosupressants
Cyclosporine RS 237 mL @ time 0, 3.5, — — NA 90

7.5, 11.5 h
RS 250 mL — — NA 64
RS 150 mL — — — 1 patient showed 168
neurological side effects
RS 250 mL — — — NA 169
RS 240 mL — — λz (cyclosporine NA 177
solution)
RS 237 mL — — Cmin NA 171
RS 176 mL t0, t + 30, t + 90 — NA 170
RS 250 mL — — NA 172
RS 240 mL For 3 days — Cmin NA 173
RS 150 mL Q3h for 30 h (P < .252) Cmin No clinical symptoms 164
RS 176 mL T0, t + 30, t + 90 — NA 175
RS 237 mL — — — — Cmin NA 175
RS 250 mL @ t-15 and t0 Median — NA 176
Other Drugs
Carbamazepine FS 300 mL — AUCss Cmaxss — Cminss NA 183

Cisapride RS 250 mL — — BP 77
HR
QTc interval
RS 250 mL — — QTc interval 185
DS 200 mL tid for 2 days — QTc interval 186
DS 200 mL tid for 2 days — QTc interval 184
Clozapine YGFJ 250 mL — No significant difference in — 194

mean plasma levels
RS 250 mL bid for 2 weeks No significant difference in CGI scores 193
mean plasma levels
CDS scores
AE profile
Digoxin RS 220 mL t-30, 1.5, 7.5 11.5 (NS) (NS) — — PR prolongation in n = 2 202
RS 240 mL tid for 5 days — Ka , Tlag , NA 92
Clrenal
Fluvoxamine RS 250 mL tid for 5 days — NA 187
Itraconazole RS 350 mL — — NA 200

DS 240 mL — (NS) — — NA 201
(continued)
1407
1408
RS 240 mL tid for 2 days — — NA 199

Losartan RS 200 mL — (NS) Tlag BP 188
Pulse
Methadone RS 200 mL t-30 — AE profile 189
Withdrawal symp.
Omeprazole RS 300 mL — — — NA 197
Scopolamine FS 150 mL — — Alertness , 190
Contentment ,
Calmness
Sertraline RS 240 mL — Mean serum trough levels AE profile 191
Sildenafil — — N=1 — BP 204
(NSR) ECG
RS 250 mL — — — NA 203
Theophylline NSR RS 100 mL — BP 195
ECG
Haloperidol RS 200 mL tid for 7 days Mean plasma levels BPR scale 196
Phenytoin RS 300 mL @ 8 AM — — 198
Repaglinide GFJ 300 mL t-1.5h — — — Blood glucose 192
HMG-CoA Reductase Inhibitors
Strong Interaction (AUC Increase ≤ 5-fold)
Simvastatin DS 200 mL 1–@1 1– (0 & 24 h) 1– 1– 1– — NA 162

2–@3 2– 2– 2– 2– —
3–@7 3– 3– 3– 3– —
Days after last
GFJ intake
RS 200 mL For 2 days — NA 72
DS 200 mL tid for 2 days — Active inhibitors 132
AUC Cmax tmax t1/2
Median
Total inhibitors
AUC Cmax tmax t1/2
Lovastatin DS 200 mL bid for 2 days — NA 160

RS 200 mL For 3 days — Active inhibitors 161
AUC Cmax tmax t1/2
—
Total inhibitors
AUC Cmax tmax t1/2
—
HMG-CoA Reductase Inhibitors
Moderate Interaction (AUC increase >2 < 5 fold)
Atorvastatin RS 250 mL tid for 2 days — NA 158

DS 200 mL tid for 2 days Median Active inhibitors 69
AUC Cmax tmax t1/2
median
Total inhibitors
AUC Cmax tmax t1/2
median
RS 250 mL tid for 4 days (NS) — — NA 159
Pravastatin RS 250 mL tid for 2 days — NA 158

DS 200 mL tid for 2 days — Active inhibitors Median1 Median 69
AUC Cmax tmax t1/2
Median —
Total inhibitors
AUC Cmax tmax t1/2
Pitavastatin RS 250 mL tid for 4 days — NA 159

Abbreviations used:
λz = elimination half-life
AE = adverse events
BG = bergamottin
bid = twice daily
BP = blood pressure
BPRS = Brief Psychiatric Rating Scale
CDS scores = Calgary Depression Scale scores
CGI scores = Clinical Global Impression Scale
Cloral = oral clearance
Clrenal = renal clearance
Cmin = trough plasma concentration
CS = commercially squeezed
DBP = diastolic blood pressure
DG = diluted grapefruit juice
DHG = dihydroxybergamottin
DS = double-strength grapefruit juice
DST = digit substitution test
DW = drowsiness
1409
(continued)
1410
EA = ethylacetate extract
ECG = electrocardiogram
F = bioavailability
F(%) = fraction absorbed
FF = fresh frozen
FFT = flicker fusion test
FS = fresh squeezed
GFJ = grapefruit juice
HR = heart rate
i.v. = intravenous dosing
Ka = absorption rate constant
Ke = elimination rate constant
mL = milliliters
NS = statistically not significant
NSR = no statistics recorded
p.o. = oral dosing
PF = particulate fraction
PSF = psychomotor function
Q3h = every 3 hours
Q6h = every 6 hours
QTC = QTc interval
RG = reconstituted grapefruit juice
RS = regular-strength grapefruit juice
SD = single dose
SF = supernatant fraction
SHR = systolic heart rate
SS = statistically significant
t + 30 = 30 minutes after drug administration
t + 2 = 2 hours afte drug administration
t + 24 = 24 hours after drug administration
t + 90 = 90-minute drug administration
t0 = concomitant intake (@time 0)
t-12 = 12 hours before drug administration
t-15 = 15 minutes before drug administration
t-30 = 30 minutes before drug administration
tid = 3 times daily
tlag = lag time
TS = thinking speed
YGFJ = yellow grapefruit juice
*P < .15. **P < .09.
REFERENCES 19. Rashid J, McKinstry C, Renwick AG, Dirnhuber M, Waller DG,

George CF. Quercetin, an in vitro inhibitor of CYP3A, does not
contribute to the interaction between nifedipine and grapefruit
1. Bailey DG, Dresser GK. Interactions between grapefruit juice
juice. Br J Clin Pharmacol. 1993;36:460-463.
and cardiovascular drugs. Am J Cardiovasc Drugs. 2004;4:281-297.
2. Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus 20. Veronese ML, Gillen LP, Burke JP, et al. Exposure-dependent
juices with felodipine and nifedipine. Lancet. 1991;337:268-269. inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit
juice. J Clin Pharmacol. 2003;43:831-839.
3. Soons PA, Vogels BA, Roosemalen MC, et al. Grapefruit juice
and cimetidine inhibit stereoselective metabolism of nitrendipine 21. Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit
in humans. Clin Pharmacol Ther. 1991;50:394-403. organic anion transporting polypeptide-mediated drug uptake to
decrease the oral availability of fexofenadine. Clin Pharmacol
4. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ. Plasma con-
Ther. 2002;71:11-20.
centrations of triazolam are increased by concominant ingestion
of grapefruit juice. Clin Pharmacol Ther. 1995;58:127-131. 22. Satoh H, Yamashita F, Tsujimoto M, et al. Citrus juices inhibit
the function of human organic anion-transporting polypeptide
5. Bailey DG, Arnold JM, Munoz C, Spence JD. Grapefruit juice-
OATP-B. Drug Metab Dispos. 2005;33:518-523.
felodipine interaction: mechanism, predictability, and effect of
naringin. Clin Pharmacol Ther. 1993;53:637-642. 23. Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-
drug interactions. Br J Clin Pharmacol. 1998;46:101-110.
6. Ducharme MP, Provenzano R, Dehoorne-Smith M, Edwards DJ.
Trough concentration of cyclosporine in blood following adminis- 24. FDA/CDER. CDER New and Generic Drug Approvals: 1998-
tration with grapefruit juice. Br J Clin Pharmacol. 1993;36:457-459. 2004. Rockville, Md: FDA/CDER; 2004.
7. Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl 25. PROCARDIA® (nifedipine) capsules for oral use. New York:
S. Interaction between grapefruit juice and midazolam in Pfizer Labs; 2000.
humans. Clin Pharmacol Ther. 1995;58:20-28. 26. Penzak SR, Acosta EP, Turner M, et al. Effect of Seville orange
8. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL. juice and grapefruit juice on indinavir pharmacokinetics. J Clin
Grapefruit juice alters terfenadine pharmacokinetics, resulting in Pharmacol. 2002;42:1165-1170.
prolongation of repolarization on the electrocardiogram. Clin 27. Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The
Pharmacol Ther. 1996;59:383-388. effect of grapefruit juice and Seville orange juice on the pharma-
9. Kupferschmidt HH, Fattinger KE, Ha HR, Follath F, Krahenbuhl cokinetics of dextromethorphan: the role of gut CYP3A and P-gly-
S. Grapefruit juice enhances the bioavailability of the HIV protease coprotein. Life Sci. 2002;71:1149-1160.
inhibitor saquinavir in man. Br J Clin Pharmacol. 1998;45:355-359. 28. De Castro WV, Mertens-Talcott S, Rubner A, Butterweck V,
10. Butterweck V, Derendorf H, Gaus W, Nahrstedt A, Schulz V, Derendorf H. Variation of flavonoids and furanocoumarins in
Unger M. Pharmacokinetic herb-drug interactions: are preventive grapefruit juices: a potential source of variability in grapefruit juice-
screenings necessary and appropriate? Planta Med. 2004;70: drug interaction studies. J Agric Food Chem. 2006;54:249-255.
784-791. 29. Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular phar-
11. Huang SM, Hall SD, Watkins P, et al. Drug interactions with macotherapy and herbal medicines: the risk of drug interaction.
herbal products and grapefruit juice: a conference report. Clin Int J Cardiol. 2005;98:1-14.
Pharmacol Ther. 2004;75:1-12. 30. Fuhr U. Drug interactions with grapefruit juice: extent, proba-
12. Dahan A, Altman H. Food-drug interaction: grapefruit juice ble mechanism and clinical relevance. Drug Saf. 1998;18:251-272.
augments drug bioavailability—mechanism, extent and rele- 31. Ameer B, Weintraub RA. Drug interactions with grapefruit
vance. Eur J Clin Nutr. 2004;58:1-9. juice. Clin Pharmacokinet. 1997;33:103-121.
13. Mitsunaga Y, Takanaga H, Matsuo H, et al. Effect of
32. Bailey DG, Arnold JM, Spence JD. Grapefruit juice and drugs:
bioflavonoids on vincristine transport across blood-brain barrier.
how significant is the interaction? Clin Pharmacokinet. 1994;26:
Eur J Pharmacol. 2000;395:193-201.
91-98.
14. Takanaga H, Ohnishi A, Matsuo H, et al. Pharmacokinetic
33. Spence JD. Drug interactions with grapefruit: whose responsibil-
analysis of felodipine-grapefruit juice interaction based on an
ity is it to warn the public? Clin Pharmacol Ther. 1997;61:395-400.
irreversible enzyme inhibition model. Br J Clin Pharmacol.
2000;49:49-58. 34. Greenblatt DJ, Patki KC, von Moltke LL, Shader RI. Drug inter-
actions with grapefruit juice: an update. J Clin Psychopharmacol.
15. Spahn-Langguth H, Langguth P. Grapefruit juice enhances
2001;21:357-359.
intestinal absorption of the P-glycoprotein substrate talinolol. Eur
J Pharm Sci. 2001;12:361-367. 35. Dresser GK, Bailey DG. The effects of fruit juices on drug dis-
16. Tian R, Koyabu N, Takanaga H, Matsuo H, Ohtani H, Sawada position: a new model for drug interactions. Eur J Clin Invest.
Y. Effects of grapefruit juice and orange juice on the intestinal 2003;33(Suppl 2):10-16.
efflux of P-glycoprotein substrates. Pharm Res. 2002;19:802-809. 36. Scora RW. On the history and origin of citrus. Bull Torrey Bot
17. Kakar SM, Paine MF, Stewart PW, Watkins PB. 6´7´- Club. 1975;102:369-375.
Dihydroxybergamottin contributes to the grapefruit juice effect. 37. Calabrese F. The history of citrus in the Mediterranean coun-
Clin Pharmacol Ther. 2004;75:569-579. tries and Europe. Proc Int Soc Citricult. 1992;1:35-38.
18. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Time course 38. Scora RW, Kumamoto J, Soost RK, Nauer EM. Contribution to
of recovery of cytochrome p450 3A function after single doses of the origin of the grapefruit, Citrus paradisi (Rutaceae). Bull Torrey
grapefruit juice. Clin Pharmacol Ther. 2003;74:121-129. Bot Club. 1982;7:170-177.

39. Nicolisi E, Deng ZN, Gentile A, La Malfa S, Continella G, 57. Bailey DG, Dresser GK, Bend JR. Bergamottin, lime juice, and
Tribulato E. Citrus phylogeny and genetic origin of important red wine as inhibitors of cytochrome P450 3A4 activity: compar-
species as investigated by molecular markers. Theor Appl Genet. ison with grapefruit juice. Clin Pharmacol Ther. 2003;73:529-537.
2000;100:1155-1166. 58. Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ, Bend
40. USDA Economic resource service. http://www.ers.usda.gov/ JR. Grapefruit-felodipine interaction: effect of unprocessed fruit and
Briefing/FruitAndTreeNuts/fruitnutpdf/grapefruit.pdf. Accessed probable active ingredients. Clin Pharmacol Ther. 2000;68:468-477.
December 2005. 59. Paine MF, Widmer WW, Hart HL, et al. A furanocoumarin-free
41. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer grapefruit juice establishes furanocoumarins as the mediators of
prevention: a review of the epidemiological evidence. Nutr the grapefruit juice-felodipine interaction. Am J Clin Nutr. 2006;
Cancer. 1992;18:1-29. 83:1097-1105.
42. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I: 60. Ubeaud G, Hagenbach J, Vandenschrieck S, Jung L, Koffel JC.
Epidemiology. Cancer Causes Control. 1991;2:325-357. In vitro inhibition of simvastatin metabolism in rat and human
43. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer preven- liver by naringenin. Life Sci. 1999;65:1403-1412.
tion: a review. J Am Diet Assoc. 1996;96:1027-1039. 61. Kamath AV, Yao M, Zhang Y, Chong S. Effect of fruit juices on
44. Arts IC, Jacobs DR Jr, Harnack LJ, Gross M, Folsom AR. Dietary the oral bioavailability of fexofenadine in rats. J Pharm Sci.
catechins in relation to coronary heart disease death among post- 2005;94:233-239.
menopausal women. Epidemiology. 2001;12:668-675. 62. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-
45. Daher CF, Abou-Khalil J, Baroody GM. Effect of acute and pharmacodynamic consequences and clinical relevance of
chronic grapefruit, orange, and pineapple juice intake on blood cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38:41-57.
lipid profile in normolipidemic rat. Med Sci Monit. 2005;11: 63. Lundahl J, Regardh CG, Edgar B, Johnsson G. Effects of grape-
BR465-BR472. fruit juice ingestion: pharmacokinetics and haemodynamics of
46. Gorinstein S, Leontowicz H, Leontowicz M, et al. Changes in intravenously and orally administered felodipine in healthy men.
plasma lipid and antioxidant activity in rats as a result of naringin Eur J Clin Pharmacol. 1997;52:139-145.
and red grapefruit supplementation. J Agric Food Chem. 2005;53: 64. Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intra-
3223-3228. venous and oral cyclosporine after administration with grapefruit
47. Fujioka K, Greenway F, Sheard J, Ying Y. The effects of grape- juice. Clin Pharmacol Ther. 1995;57:485-491.
fruit on weight and insulin resistance: relationship to the meta- 65. Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metab-
bolic syndrome. J Med Food. 2006;9:49-54. olism and transport. Clin Pharmacokinet. 2003;42:1071-1088.
48. Lesser PF. Florida grapefruit juice developments. In: Second 66. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases
International Fruit-Juice Conference; October 7, 1997; felodipine oral availability in humans by decreasing intestinal
Amsterdam, The Netherlands. CYP3A protein expression. J Clin Invest. 1997;99:2545-2553.
49. Berhow M, Kanes K, Vandercook C. Survey of phenolic 67. Guo LQ, Fukuda K, Ohta T, Yamazoe Y. Role of fura-
compounds produced in citrus. Technical Bulletin 1856, US nocoumarin derivatives on grapefruit juice-mediated inhibition
Department of Agriculture; 1998. of human CYP3A activity. Drug Metab Dispos. 2000;28:766-771.
50. Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, et al. 68. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases
Mechanisms of enhanced oral availability of CYP3A4 substrates felodipine oral availability in humans by decreasing intestinal
by grapefruit constituents: decreased enterocyte CYP3A4 concen- CYP3A protein expression. J Clin Invest. 1997;99:2545-2553.
tration and mechanism-based inactivation by furanocoumarins. 69. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases
Drug Metab Dispos. 1997;25:1228-1233. serum concentrations of atorvastatin and has no effect on pravas-
51. Eagling VA, Profit L, Back DJ. Inhibition of the CYP3A4- tatin. Clin Pharmacol Ther. 1999;66:118-127.
mediated metabolism and P-glycoprotein-mediated transport of 70. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin
the HIV-1 protease inhibitor saquinavir by grapefruit juice com- interaction: effect on serum concentrations of simvastatin, sim-
ponents. Br J Clin Pharmacol. 1999;48:543-552. vastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol
52. He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF. Ther. 1998;64:477-483.
Inactivation of cytochrome P450 3A4 by bergamottin, a compo- 71. Lilja JJ, Kivisto KT, Backman JT, Neuvonen PJ. Effect of grape-
nent of grapefruit juice. Chem Res Toxicol. 1998;11:252-259. fruit juice dose on grapefruit juice-triazolam interaction: repeated
53. Ghosal A, Satoh H, Thomas PE, Bush E, Moore D. Inhibition consumption prolongs triazolam half-life. Eur J Clin Pharmacol.
and kinetics of cytochrome P4503A activity in microsomes from 2000;56:411-415.
rat, human, and cdna-expressed human cytochrome P450. Drug 72. Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular con-
Metab Dispos. 1996;24:940-947. sumption of grapefruit juice on the pharmacokinetics of simvas-
54. Ha HR, Chen J, Leuenberger PM, Freiburghaus AU, Follath F. tatin. Br J Clin Pharmacol. 2004;58:56-60.
In vitro inhibition of midazolam and quinidine metabolism by 73. Tassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y.
flavonoids. Eur J Clin Pharmacol. 1995;48:367-371. Inhibition selectivity of grapefruit juice components on human
55. Guo LQ, Taniguchi M, Xiao YQ, Baba K, Ohta T, Yamazoe Y. cytochromes P450. Arch Biochem Biophys. 2000;378:356-363.
Inhibitory effect of natural furanocoumarins on human microsomal 74. Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfi-
cytochrome P450 3A activity. Jpn J Pharmacol. 2000;82:122-129. ram, itraconazole, grapefruit juice and erythromycin on the phar-
56. Paine MF, Criss AB, Watkins PB. Two major grapefruit juice macokinetics of quinidine. Br J Clin Pharmacol. 1999;48:829-838.
components differ in intestinal CYP3A4 inhibition kinetic and 75. Fuhr U, Klittch K, Atab AH. Inhibitory effect of grapefruit
binding properties. Drug Metab Dispos. 2004;32:1146-1153. juice and its bitter principle, naringenin, on CYP1A2 dependent
1412 • J Clin Pharmacol 2006;46:1390-1416

metabolism of caffeine in man. Br J Clin Pharmacol. 1993;35: 93. Zhou S, Lim LY, Chowbay B. Herbal modulation of P-
431-436. glycoprotein. Drug Metab Rev. 2004;36:57-104.
76. Zhou S, Chan E, Lim LY, et al. Therapeutic drugs that behave 94. Zhang Y, Benet LZ. The gut as a barrier to drug absorption:
as mechanism-based inhibitors of cytochrome P450 3A4. Curr combined role of cytochrome P450 3A and P-glycoprotein. Clin
Drug Metab. 2004;5:415-442. Pharmacokinet. 2001;40:159-168.
77. Gross AS, Goh YD, Addison RS, Shenfield GM. Influence of 95. Kane GC, Lipsky JJ. Drug-grapefruit juice interaction. Mayo
grapefruit juice on cisapride pharmacokinetics. Clin Pharmacol Clin Proc. 2000;75:933-942.
Ther. 1999;65:395-401. 96. Mikkaichi T, Suzuki T, Tanemoto M, Ito S, Abe T. The organic
78. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, anion transporter (OATP) family. Drug Metab Pharmacokinet.
Gottesman MM. Biochemical, cellular, and pharmacological 2004;19:171-179.
aspects of the multidrug transporter. Annu Rev Pharmacol 97. Kim RB. Organic anion-transporting polypeptide (OATP)
Toxicol. 1999;39:361-398. transporter family and drug disposition. Eur J Clin Invest. 2003;
79. Schinkel AH, Jonker JW. Mammalian drug efflux transporters 33(Suppl 2):1-5.
of the ATP binding cassette (ABC) family: an overview. Adv Drug 98. Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt
Deliv Rev. 2003;55:3-29. transporters in normal physiology and liver disease. Gastroenterol-
80. Gottesman MM, Pastan I. Biochemistry of multidrug resis- ogy. 2004;126:322-342.
tance mediated by the multidrug transporter. Annu Rev Biochem. 99. Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I.
1993;62:385-427. Involvement of human organic anion transporting polypeptide
81. Schinkel AH. The roles of P-glycoprotein and MRP1 in the OATP-B (SLC21A9) in pH-dependent transport across intestinal
blood-brain and blood-cerebrospinal fluid barriers. Adv Exp Med apical membrane. J Pharmacol Exp Ther. 2003;306:703-708.
Biol. 2001;500:365-372. 100. Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ.
82. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate and tis- Itraconazole increases but grapefruit juice greatly decreases plasma
sue distribution of cytochrome P450 and P-glycoprotein: implica- concentrations of celiprolol. Clin Pharmacol Ther. 2003;73:192-198.
tions for drug delivery and activity in cancer chemotherapy. Mol 101. Lilja JJ, Juntti-Patinen L, Neuvonen PJ. Orange juice substan-
Carcinogen. 1995;13:129-134. tially reduces the bioavailability of the beta-adrenergic-blocking
83. Soldner A, Christians U, Susanto M, Wacher VJ, Silverman JA, agent celiprolol. Clin Pharmacol Ther. 2004;75:184-190.
Benet LZ. Grapefruit juice activates P-glycoprotein-mediated drug 102. Karlsson J, Kuo SM, Ziemniak J, Artursson P. Transport of
transport. Pharm Res. 1999;16:478-485. celiprolol across human intestinal epithelial (Caco-2) cells: medi-
84. Malhotra S, Bailey DG, Paine MF, Watkins PB. Seville orange ation of secretion by multiple transporters including P-glycoprotein.
juice-felodipine interaction: comparison with dilute grapefruit Br J Pharmacol. 1993;110:1009-1016.
juice and involvement of furocoumarins. Clin Pharmacol Ther. 103. Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB.
2001;69:14-23. OATP and P-glycoprotein transporters mediate the cellular uptake
85. Takanaga H, Ohnishi A, Matsu H, Sawada Y. Inhibition of vin- and excretion of fexofenadine. Drug Metab Dispos. 1999;27:866-871.
blastine efflux mediated by P-glycoprotein by grapefruit juice 104. Schwarz UI, Seemann D, Oertel R, et al. Grapefruit juice
components in Caco-2 cells. Biol Pharm Bull. 1998;21:1062-1066. ingestion significantly reduces talinolol bioavailability. Clin
86. Ikegawa T, Ushigome F, Koyabu N, Morimoto S, Shoyama Y, Pharmacol Ther. 2005;77:291-301.
Naito M. Inhibition of P-glycoprotein by orange juice components, 105. Saito M, Hirata-Koizumi M, Matsumoto M, Urano T, Hasegawa R.
polymethoxyflavones in adriamycin-resistant human myeloge- Undesirable effects of citrus juice on the pharmacokinetics of
nous leukemia (K562/ADM) cells. Cancer Lett. 2000;160:21-28. drugs: focus on recent studies. Drug Saf. 2005;28:677-694.
87. Ohnishi A, Matsuo H, Yamada S, Takanaga H, Morimoto S, 106. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of
Shoyama Y. Effect of furanocoumarin derivatives in grapefruit in vitro and in vivo drug-drug interaction studies: a PhRMA per-
juice on the uptake of vinblastine by Caco-2 cells and on the activ- spective. J Clin Pharmacol. 2003;43:443-469.
ity of cytochrome P450 3A4. Br J Pharmacol. 2000;130:1369-1377. 107. Clifford CP, Adams DA, Murray S, et al. The cardiac effects
88. Spahn-Langguth H, Langguth P. Grapefruit juice enhances of terfenadine after inhibition of its metabolism by grapefruit
intestinal absorption of P-glycoprotein-mediated substrate tali- juice. Eur J Clin Pharmacol. 1997;52:311-315.
nolol. Eur J Pharm Sci. 2001;12:361-367. 108. Honig PK, Wortham DC, Lazarev A, Cantilena LR. Grapefruit
89. Xu J, Go ML, Lim LY. Modulation of digoxin transport across juice alters the systemic bioavailability and cardiac repolarization of
Caco-2 cell monolayers by citrus fruit juices: lime, lemon, grape- terfenadine in poor metabolizers of terfenadine. J Clin Pharmacol.
fruit, and pummelo. Pharm Res. 2003;20:169-176. 1996;36:345-351.
90. Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6´,7´- 109. Rau SE, Bend JR, Arnold MO, Tran LT, Spence JD, Bailey DG.
Dihydroxybergamottin in grapefruit juice and Seville orange Grapefruit juice-terfenadine single-dose interaction: magnitude,
juice: effects on cyclosporine disposition, enterocyte CYP3A4, mechanism, and relevance. Clin Pharmacol Ther. 1997;61:401-409.
and P-glycoprotein. Clin Pharmacol Ther. 1999;65:237-244. 110. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL.
91. Josefsson M, Zackrisson AL, Ahlner J. Effect of grapefruit juice Grapefruit juice alters terfenadine pharmacokinetics, resulting in
on the pharmacokinetics of amlodipine in healthy volunteers. Eur prolongation of repolarization on the electrocardiogram. Clin
J Clin Pharmacol. 1996;51:189-193. Pharmacol Ther. 1996;59:383-388.
92. Parker RB, Yates CR, Soberman JE, Laizure SC. Effects of 111. Banfield C, Gupta S, Marino M, Lim J, Affrime M. Grapefruit
grapefruit juice on intestinal P-glycoprotein: evaluation using juice reduces the oral bioavailability of fexofenadine but not
digoxin in humans. Pharmacotherapy. 2003;23:979-987. desloratadine. Clin Pharmacokinet. 2002;41:311-318.

112. Cheng KL, Nafziger AN, Peloquin CA, Amsden GW. Effect of 131. Culm-Merdek KE, von Moltke LL, Gan L, et al. Effect of
grapefruit juice on clarithromycin pharmacokinetics. Antimicrob extended exposure to grapefruit juice on cytochrome P450 3A
Agents Chemother. 1998;42:927-979. activity in humans: comparison with ritonavir. Clin Pharmacol
113. Kanazawa S, Ohkubo T, Sugawara K. The effects of grapefruit Ther. 2006;79:243-254.
juice on the pharmacokinetics of erythromycin. Eur J Clin 132. Lilja JJ, Kivisto KT, Backman JT, Lamberg TS, Neuvonen PJ.
Pharmacol. 2001;56:799-803. Grapefruit juice substantially increases plasma concentrations of
114. Shi J, Montay G, Leroy B, Bhargava VO. Effects of itracona- buspirone. Clin Pharmacol Ther. 1998;64:655-660.
zole or grapefruit juice on the pharmacokinetics of telithromycin. 133. Ozdemir M, Aktan Y, Boydag BS, Cingi MI, Musmul A.
Pharmacotherapy. 2005;25:42-51. Interaction between grapefruit juice and diazepam in humans.
115. Merkel U, Sigusch H, Hoffmann A. Grapefruit juice inhibits Eur J Drug Metab Pharmacokinet. 1998;23:55-59.
7-hydroxylation of coumarin in healthy volunteers. Eur J Clin 134. Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S,
Pharmacol. 1994;46:175-177. Friedman HL. Lack of effect of grapefruit juice on the pharmacoki-
116. Runkel M, Tegtmeier M, Legrum W. Metabolic and analytical netics and pharmacodynamics of amlodipine. Br J Clin Pharmacol.
interactions of grapefruit juice and 1,2-benzopyrone (coumarin) 2000;50:455-463.
in man. Eur J Clin Pharmacol. 1996;50:225-230. 135. Christensen H, Asberg A, Holmboe AB, Berg KJ.
117. Runkel M, Bourian M, Tegtmeier M, Legrum W. The character Coadministration of grapefruit juice increases systemic exposure
of inhibition of the metabolism of 1,2-benzopyrone (coumarin) by of diltiazem in healthy volunteers. Eur J Clin Pharmacol. 2002;58:
grapefruit juice in human. Eur J Clin Pharmacol. 1997;53:265-269. 515-520.
118. Sullivan DM, Ford MA, Boyden TW. Grapefruit juice and the 136. Sigusch H, Henschel L, Kraul H, Merkel U, Hoffmann A.
response to warfarin. Am J Health Syst Pharm. 1998;55:1581-1583. Lack of effect of grapefruit juice on diltiazem bioavailability in
119. van Agtmael MA, Gupta V, van der Wosten TH, Rutten JP, normal subjects. Pharmazie. 1994;49:675-679.
van Boxtel CJ. Grapefruit juice increases the bioavailability of 137. Fuhr U, Maier-Bruggemann A, Blume H, et al. Grapefruit juice
artemether. Eur J Clin Pharmacol. 1999;55:405-410. increases oral nimodipine bioavailability. Int J Clin Pharmacol
120. van Agtmael MA, Gupta V, van der Graaf CA, van Boxtel CJ. Ther. 1998;36:126-132.
The effect of grapefruit juice on the time-dependent decline of 138. Rashid J, McKinstry C, Renwick AG, Dirnhuber M, Waller
artemether plasma levels in healthy subjects. Clin Pharmacol DG, George CF. Quercetin, an in vitro inhibitor of CYP3A, does
Ther. 1999;66:408-414. not contribute to the interaction between nifedipine and grape-
121. Charbit B, Becquemont L, Lepere B, Peytavin G, Funck- fruit juice. Br J Clin Pharmacol. 1993;36:460-463.
Brentano C. Pharmacokinetic and pharmacodynamic interaction 139. Sigusch H, Hippius M, Henschel L, Kaufmann K, Hoffmann
between grapefruit juice and halofantrine. Clin Pharmacol Ther. A. Influence of grapefruit juice on the pharmacokinetics of a slow
2002;72:514-523. release nifedipine formulation. Pharmazie. 1994;49:522-524.
122. Min DI, Ku YM, Geraets DR, Lee H. Effect of grapefruit juice 140. Hashimoto K, Shirafuji T, Sekino H, et al. Interaction of cit-
on the pharmacokinetics and pharmacodynamics of quinidine in rus juices with pranidipine, a new 1,4-dihydropyridine calcium
healthy volunteers. J Clin Pharmacol. 1996;36:469-476. antagonist, in healthy subjects. Eur J Clin Pharmacol. 1998;54:
123. Ho PC, Chalcroft SC, Coville PF, Wanwimolruk S. Grapefruit 753-760.
juice has no effect on quinine pharmacokinetics. Eur J Clin 141. Fuhr U, Muller-Peltzer H, Kern R, et al. Effects of grapefruit
Pharmacol. 1999;55:393-398. juice and smoking on verapamil concentrations in steady state.
124. Nagy J, Schipper HG, Koopmans RP, Butter JJ, Van Boxtel CJ, Eur J Clin Pharmacol. 2002;58:45-53.
Kager PA. Effect of grapefruit juice or cimetidine coadministra- 142. Ho PC, Ghose K, Saville D, Wanwimolruk S. Effect of grape-
tion on albendazole bioavailability. Am J Trop Med Hyg. fruit juice on pharmacokinetics and pharmacodynamics of vera-
2002;66:260-263. pamil enantiomers in healthy volunteers. Eur J Clin Pharmacol.
125. Castro N, Jung H, Medina R, Gonzalez-Esquivel D, Lopez M, 2000;56:693-698.
Sotelo J. Interaction between grapefruit juice and praziquantel in 143. Zaidenstein R, Dishi V, Gips M, et al. The effect of grapefruit
humans. Antimicrob Agents Chemother. 2002;46:1614-1616. juice on the pharmacokinetics of orally administered verapamil.
126. Yasui N, Kondo T, Furukori H, et al. Effects of repeated inges- Eur J Clin Pharmacol. 1998;54:337-340.
tion of grapefruit juice on the single and multiple oral-dose 144. Lundahl JU, Regardh CG, Edgar B, Johnsson G. The interac-
pharmacokinetics and pharmacodynamics of alprazolam. psy- tion effect of grapefruit juice is maximal after the first glass. Eur J
chopharmacology (Berl). 2000;150:185-190. Clin Pharmacol. 1998;54:75-81.
127. Andersen V, Pedersen N, Larsen NE, Sonne J, Larsen S. 145. Bailey DG, Arnold JM, Munoz C, Spence JD. Grapefruit
Intestinal first pass metabolism of midazolam in liver cirrhosis: juice–felodipine interaction: mechanism, predictability, and
effect of grapefruit juice. Br J Clin Pharmacol. 2002;54:120-124. effect of naringin. Clin Pharmacol Ther. 1993;53:637-642.
128. Vanakoski J, Mattila MJ, Seppala T. Grapefruit juice does not 146. Bailey DG, Bend JR, Arnold JM, Tran LT, Spence JD.
enhance the effects of midazolam and triazolam in man. Eur J Clin Erythromycin-felodipine interaction: magnitude, mechanism,
Pharmacol. 1996;50:501-508. and comparison with grapefruit juice. Clin Pharmacol Ther. 1996;
129. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ. Plasma 60:25-33.
concentrations of triazolam are increased by concomitant inges- 147. Dresser GK, Bailey DG, Carruthers SG. Grapefruit juice–felodip-
tion of grapefruit juice. Clin Pharmacol Ther. 1995;58:127-131. ine interaction in the elderly. Clin Pharmacol Ther. 2000;68:28-34.
130. Sugimoto K, Araki N, Ohmori M, et al. Interaction between 148. Goosen TC, Cillie D, Bailey DG, et al. Bergamottin contribu-
grapefruit juice and hypnotic drugs: comparison of triazolam and tion to the grapefruit juice–felodipine interaction and disposition
quazepam. Eur J Clin Pharmacol. 2006;62:209-215. in humans. Clin Pharmacol Ther. 2004;76:607-617.
1414 • J Clin Pharmacol 2006;46:1390-1416

149. Edgar B, Bailey D, Bergstrand R, Johnsson G, Regardh CG. 167. Lilja JJ, Laitinen K, Neuvonen PJ. Effects of grapefruit juice
Acute effects of drinking grapefruit juice on the pharmacokinetics on the absorption of levothyroxine. Br J Clin Pharmacol. 2005;60:
and dynamics of felodipine—and its potential clinical relevance. 337-341.
Eur J Clin Pharmacol. 1992;42:313-317. 168. Ioannides-Demos LL, Christophidis N, Ryan P, Angelis P,
150. Bailey DG, Arnold JM, Bend JR, Tran LT, Spence JD. Liolios L, McLean AJ. Dosing implications of a clinical interac-
Grapefruit juice–felodipine interaction: reproducibility and char- tion between grapefruit juice and cyclosporine and metabolite
acterization with the extended release drug formulation. Br J Clin concentrations in patients with autoimmune diseases. J Rheumatol.
Pharmacol. 1995;40:135-140. 1997;24:49-54.
151. Uno T, Ohkubo T, Sugawara K, Higashiyama A, Motomura S, 169. Yee GC, Stanley DL, Pessa LJ, et al. Effect of grapefruit juice
Ishizaki T. Effects of grapefruit juice on the stereoselective disposi- on blood cyclosporin concentration. Lancet. 1995;345:955-956.
tion of nicardipine in humans: evidence for dominant presystemic 170. Ku YM, Min DI, Flanigan M. Effect of grapefruit juice on the
elimination at the gut site. Eur J Clin Pharmacol. 2000;56:643-649. pharmacokinetics of microemulsion cyclosporine and its metabo-
152. Bailey DG, Arnold JM, Strong HA, Munoz C, Spence JD. lite in healthy volunteers: does the formulation difference matter?
Effect of grapefruit juice and naringin on nisoldipine pharmaco- J Clin Pharmacol. 1998;38:959-965.
kinetics. Clin Pharmacol Ther. 1993;54:589-594. 171. Min DI, Ku YM, Perry PJ, et al. Effect of grapefruit juice
153. Takanaga H, Ohnishi A, Murakami H, et al. Relationship on cyclosporine pharmacokinetics in renal transplant patients.
between time after intake of grapefruit juice and the effect on Transplantation. 1996;62:123-125.
pharmacokinetics and pharmacodynamics of nisoldipine in 172. Hermann M, Asberg A, Reubsaet JL, Sather S, Berg KJ,
healthy subjects. Clin Pharmacol Ther. 2000;67:201-214. Christensen H. Intake of grapefruit juice alters the metabolic pat-
154. Uno T, Ohkubo T, Motomura S, Sugawara K. Effect of grape- tern of cyclosporin A in renal transplant recipients. Int J Clin
fruit juice on the disposition of manidipine enantiomers in Pharmacol Ther. 2002;40:451-456.
healthy subjects. Br J Clin Pharmacol. 2006;61:533-537. 173. Brunner LJ, Munar MY, Vallian J, et al. Interaction between
155. Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, cyclosporine and grapefruit juice requires long-term ingestion in
Taburet AM. Single-dose pharmacokinetics of amprenavir coad- stable renal transplant recipients. Pharmacotherapy. 1998;18:23-29.
ministered with grapefruit juice. Antimicrob Agents Chemother. 174. Lee M, Min DI, Ku YM, Flanigan M. Effect of grapefruit juice
2002;46:1589-1590. on pharmacokinetics of microemulsion cyclosporine in African
156. Shelton MJ, Wynn HE, Hewitt RG, DiFrancesco R. Effects of American subjects compared with Caucasian subjects: does eth-
grapefruit juice on pharmacokinetic exposure to indinavir in HIV- nic difference matter? J Clin Pharmacol. 2001;41:317-323.
positive subjects. J Clin Pharmacol. 2001;41:435-442. 175. Ducharme MP, Provenzano R, Dehoorne-Smith M, Edwards
157. Hugen PW, Burger DM, Koopmans PP, et al. Saquinavir soft- DJ. Trough concentrations of cyclosporine in blood following
gel capsules (Fortovase) give lower exposure than expected, even administration with grapefruit juice. Br J Clin Pharmacol. 1993;
after a high-fat breakfast. Pharm World Sci. 2002;24:83-86. 36:457-459.
158. Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of 176. Bistrup C, Nielsen FT, Jeppesen UE, Dieperink H. Effect of
grapefruit juice on pharmacokinetics of atorvastatin and pravas- grapefruit juice on Sandimmun Neoral absorption among stable renal
tatin in Japanese. Br J Clin Pharmacol. 2004;57:448-455. allograft recipients. Nephrol Dial Transplant. 2001;16:373-377.
159. Ando H, Tsuruoka S, Yanagihara H, et al. Effects of grapefruit 177. Brunner LJ, Pai KS, Munar MY, Lande MB, Olyaei AJ, Mowry
juice on the pharmacokinetics of pitavastatin and atorvastatin. Br JA. Effect of grapefruit juice on cyclosporin A pharmacokinetics
J Clin Pharmacol. 2005;60:494-497. in pediatric renal transplant patients. Pediatr Transplant. 2000;4:
160. Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly 313-321.
increases serum concentrations of lovastatin and lovastatin acid. 178. Reif S, Nicolson MC, Bisset D, et al. Effect of grapefruit juice
Clin Pharmacol Ther. 1998;63:397-402. intake on etoposide bioavailability. Eur J Clin Pharmacol. 2002;
161. Rogers JD, Zhao J, Liu L, et al. Grapefruit juice has minimal 58:491-494.
effects on plasma concentrations of lovastatin-derived 3-hydroxy- 179. Maish WA, Hampton EM, Whitsett TL, Shepard JD, Lovallo
3-methylglutaryl coenzyme A reductase inhibitors. Clin Pharmacol WR. Influence of grapefruit juice on caffeine pharmacokinetics
Ther. 1999;66:358-366. and pharmacodynamics. Pharmacotherapy. 1996;16:1046-1052.
162. Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grape- 180. Fuhr U, Klittich K, Staib AH. Inhibitory effect of grapefruit juice
fruit juice on the pharmacokinetics of the CYP3A4 substrate sim- and its bitter principal, naringenin, on CYP1A2 dependent metabo-
vastatin. Clin Pharmacol Ther. 2000;68:384-390. lism of caffeine in man. Br J Clin Pharmacol. 1993;35:431-436.
163. Schubert W, Cullberg G, Edgar B, Hedner T. Inhibition of 17 181. Lilja JJ, Raaska K, Neuvonen PJ. Effects of grapefruit juice on
beta-estradiol metabolism by grapefruit juice in ovariectomized the pharmacokinetics of acebutolol. Br J Clin Pharmacol. 2005;
women. Maturitas. 1994;20:155-163. 60:659-663.
164. Hollander AA, van Rooij J, Lentjes GW, et al. The effect of 182. Libersa CC, Brique SA, Motte KB, et al. Dramatic inhibition
grapefruit juice on cyclosporine and prednisone metabolism in of amiodarone metabolism induced by grapefruit juice. Br J Clin
transplant patients. Clin Pharmacol Ther. 1995;57:318-324. Pharmacol. 2000;49:373-378.
165. Weber A, Jager R, Borner A, et al. Can grapefruit juice influence 183. Garg SK, Kumar N, Bhargava VK, Prabhakar SK. Effect of
ethinylestradiol bioavailability? Contraception. 1996;53:41-47. grapefruit juice on carbamazepine bioavailability in patients with
166. Varis T, Kivisto KT, Neuvonen PJ. Grapefruit juice can epilepsy. Clin Pharmacol Ther. 1998;64:286-288.
increase the plasma concentrations of oral methylprednisolone. 184. Desta Z, Kivisto KT, Lilja JJ, et al. Stereoselective pharmaco-
Eur J Clin Pharmacol. 2000;56:489-493. kinetics of cisapride in healthy volunteers and the effect of

repeated administration of grapefruit juice. Br J Clin Pharmacol. 195. Fuhr U, Maier A, Keller A, Steinijans VW, Sauter R, Staib
2001;52:399-407. AH. Lacking effect of grapefruit juice on theophylline pharmaco-
185. Offman EM, Freeman DJ, Dresser GK, Munoz C, Bend JR, kinetics. Int J Clin Pharmacol Ther. 1995;33:311-314.
Bailey DG. Red wine–cisapride interaction: comparison with 196. Yasui N, Kondo T, Suzuki A, et al. Lack of significant phar-
grapefruit juice. Clin Pharmacol Ther. 2001;70:17-23. macokinetic interaction between haloperidol and grapefruit juice.
186. Kivisto KT, Lilja JJ, Backman JT, Neuvonen PJ. Repeated con- Int Clin Psychopharmacol. 1999;14:113-118.
sumption of grapefruit juice considerably increases plasma con- 197. Tassaneeyakul W, Vannaprasaht S, Yamazoe Y. Formation of
centrations of cisapride. Clin Pharmacol Ther. 1999;66:448-453. omeprazole sulphone but not 5-hydroxyomeprazole is inhibited
187. Hori H, Yoshimura R, Ueda N, et al. Grapefruit juice– by grapefruit juice. Br J Clin Pharmacol. 2000;49:139-144.
fluvoxamine interaction: is it risky or not? J Clin Psychopharma- 198. Kumar N, Garg SK, Prabhakar S. Lack of pharmacokinetic
col. 2003;23:422-424. interaction between grapefruit juice and phenytoin in healthy
188. Zaidenstein R, Soback S, Gips M, et al. Effect of grapefruit male volunteers and epileptic patients. Methods Find Exp Clin
juice on the pharmacokinetics of losartan and its active metabolite Pharmacol. 1999;21:629-632.
E3174 in healthy volunteers. Ther Drug Monit. 2001;23:369-373. 199. Gubbins PO, McConnell SA, Gurley BJ, et al. Influence of
189. Benmebarek M, Devaud C, Gex-Fabry M, et al. Effects of grapefruit juice on the systemic availability of itraconazole oral
grapefruit juice on the pharmacokinetics of the enantiomers of solution in healthy adult volunteers. Pharmacotherapy. 2004;24:
methadone. Clin Pharmacol Ther. 2004;76:55-63. 460-467.
190. Ebert U, Oertel R, Kirch W. Influence of grapefruit juice on 200. Kawakami M, Suzuki K, Ishizuka T, Hidaka T, Matsuki Y,
scopolamine pharmacokinetics and pharmacodynamics in healthy Nakamura H. Effect of grapefruit juice on pharmacokinetics of
male and female subjects. Int J Clin Pharmacol Ther. 2000;38: itraconazole in healthy subjects. Int J Clin Pharmacol Ther. 1998;
523-531. 36:306-308.
191. Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BC. The 201. Penzak SR, Gubbins PO, Gurley BJ, Wang PL, Saccente M.
effects of grapefruit juice on sertraline metabolism: an in vitro and Grapefruit juice decreases the systemic availability of itraconazole
in vivo study. Clin Ther. 1999;21:1890-1899. capsules in healthy volunteers. Ther Drug Monit. 1999;21:304-309.
192. Bidstrup TB, Damkier P, Olsen AK, Ekblom M, Karlsson A, 202. Becquemont L, Verstuyft C, Kerb R, et al. Effect of grapefruit
Brosen K. The impact of CYP2C8 polymorphism and grapefruit juice on digoxin pharmacokinetics in humans. Clin Pharmacol
juice on the pharmacokinetics of repaglinide. Br J Clin Pharmacol. Ther. 2001;70:311-316.
2006;61:49-57. 203. Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al.
193. Lane HY, Jann MW, Chang YC, et al. Repeated ingestion of Effects of grapefruit juice on the pharmacokinetics of sildenafil.
grapefruit juice does not alter clozapine’s steady-state plasma levels, Clin Pharmacol Ther. 2002;71:21-29.
effectiveness, and tolerability. J Clin Psychiatry. 2001;62:812-817. 204. Lee M, Min DI. Determination of sildenafil citrate in plasma
194. Vandel S, Netillard C, Perault MC, Bel AM. Plasma levels of by high-performance liquid chromatography and a case for the
clozapine and desmethylclozapine are unaffected by concomitant potential interaction of grapefruit juice with sildenafil citrate.
ingestion of grapefruit juice. Eur J Clin Pharmacol. 2000;56:347-348. Ther Drug Monit. 2001;23:21-26.
1416 • J Clin Pharmacol 2006;46:1390-1416

Grapefruit-Drug Interactions Can Interactions With Drugs Be Avoided

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Grapefruit-Drug Interactions Can Interactions With Drugs Be Avoided

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Grapefruit-Drug Interactions: Can Interactions With Drugs Be Avoided?

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Grapefruit-Drug Interactions: Can

1390 • J Clin Pharmacol 2006;46:1390-1416

DRUG INTERACTIONS 1391

1392 • J Clin Pharmacol 2006;46:1390-1416

DRUG INTERACTIONS 1393

1394 • J Clin Pharmacol 2006;46:1390-1416

DRUG INTERACTIONS 1395

1396 • J Clin Pharmacol 2006;46:1390-1416

Where applicable, the clinical relevance of GFJ Antimalaria Drugs

DRUG INTERACTIONS 1397

nifedipine and GFJ. Felodipine,17,58,63,68,84,91,141-150 Antitumor Drugs

Amprenavir155 and indinavir26,156 did not induce Over-the-Counter Drugs

Grapefruit juice did not affect 17-beta estradiol163 or Antiarrhythmics

Eleven out of a total of 13 studies reported increased Other Drugs

1398 • J Clin Pharmacol 2006;46:1390-1416

DRUG INTERACTIONS 1399

Moderate Interaction (AUC Increase >2- < 5-fold)

Grapefruit Juice Parameters Pharmacokinetics

Terfenadine DS 240 mL t = 0 or t + 2 Concentrations not SS increase in QTc interval 8

Grapefruit Juice Parameters Pharmacokinetics

Desloratadine DS 240 mL tid — ECG 111

No or Weak Interaction (AUC Increase ≤ 2-fold)

Grapefruit Juice Parameters Pharmacokinetics

Calithromycin FS 240 mL t0 and t-24 — NA 112

No or Weak Interaction (AUC Increase ≤ 2-fold)

Grapefruit Juice Parameters Pharmacokinetics

Warfarin FS 237 mL tid (for — — — — Prothrombine time , 118

Strong Interaction (AUC Increase ≥ 5-fold)

Grapefruit Juice Parameters Pharmacokinetics

Halofantrine RS 250 mL @8:00 AM — QTc prolongation 121

Grapefruit Juice Parameters Pharmacokinetics

Artemether DS 350 mL concomitant — No sign of bradycardia, 119

Grapefruit Juice Parameters Pharmacokinetics

Qunidine RS 250 mL bid — Median Median Clren NA 74

Moderate Interaction (AUC Increase >2- < 5-fold)

Grapefruit Juice Parameters Pharmacokinetics

Albendazole DS 250 mL — — NA 124

No or Weak Interaction (AUC Increase ? 2-fold)

Grapefruit Juice Parameters Pharmacokinetics

Praziquamtele CS 250 mL — — NA 125

Grapefruit Juice Parameters Pharmacokinetics

Buspirone DS 200 mL bid for 2 days — SOE PSF 132

Grapefruit Juice Parameters Pharmacokinetics

Midazolam 1–RS 1–300 mL 1 1- — — — 1- DST 128

No or Weak Interaction (AUC Increase ≤ 2-fold)

Grapefruit Juice Parameters Pharmacokinetics

Triazolam 1–RS 1–200 mL 1–qd 1– 1– 1– — 1 & 2- 71

Alprazolam 1–RS 1–200 mL 1–tid –8 days + 1– 1– 1– — 1- PSF 126

Quazepam RS 250 mL t = 0, t = 4, (NS) — DSST 130

Moderate Interaction (AUC Increase >2- < 5-fold)

Grapefruit Juice Parameters Pharmacokinetics

Felodipine 1–RS 1–250 mL 1– — 1– 1– 1– 1– — 1–NA 148

Grapefruit Juice Parameters Pharmacokinetics

Nitrendipine RFG 150 mL — — HR , BP 3

Grapefruit Juice Parameters Pharmacokinetics

Pranidipine RS 250 mL — — BP , HR 140

Grapefruit Juice Parameters Pharmacokinetics

Diltiazem RS 250 mL — (NS) — NA 135