asian journal of pharmaceutical sciences 12 (2017) 464–469

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Original Research Paper

Effects of tomato juice on the pharmacokinetics

of CYP3A4-substrate drugs

Atsuko Ohkubo 1, Tomomi Chida 2, Hidetomo Kikuchi, Tadashi Tsuda,

Katsuyoshi Sunaga *
Laboratory of Pharmacotherapy, Department of Clinical Dietetics and Human Nutrition, Faculty of
Pharmaceutical Sciences, Josai University, Keyakidai 1-1, Sakado, Saitama 350-0295, Japan

A R T I C L E I N F O A B S T R A C T

Article history: We previously demonstrated that tomato juice (TJ) contains potent mechanism-based in-
Received 12 November 2016 hibitor(s) of CYP3A4. In this study, we investigated the effects of TJ and grapefruit juice (GFJ)
Received in revised form 29 April on the pharmacokinetics of the CYP3A4-substrate drugs, nifedipine (NFP) and midazolam
2017 (MDZ), in male Wistar rats. Oral administration of GFJ 90 min before the intraduodenal ad-
Accepted 8 May 2017 ministration of NFP or MDZ increased the area under the concentration–time curves (AUCs)
Available online 12 May 2017 of NFP and MDZ by 32.4% and 89.4%, respectively. TJ increased MDZ blood concentrations
and AUC after intraduodenal MDZ administration; however, it had no effect on NFP. When
Keywords: MDZ and NFP were intravenously administered, GFJ significantly increased the AUC of MDZ,
Food–drug interactions but only slightly increased that of NFP. In contrast, TJ only slightly increased the AUC of MDZ.
Tomato juice These results suggest that, similar to GFJ, TJ influences the pharmacokinetics of CYP3A4-
Grapefruit juice substrate drugs; however, it may be a drug-dependent partial effect.
Nifedipine © 2017 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. This
Midazolam is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
Pharmacokinetic interactions licenses/by-nc-nd/4.0/).

in clinically important drug interactions. These food–drug in-

1. Introduction teractions are a critical aspect of pharmacotherapy, with
potential impacts on the pharmacokinetics and pharmacody-
Many food and/or beverages have recently been found to in- namics of drugs. Pharmacokinetic interactions can involve
fluence drug metabolism and transport, sometimes resulting enzymes and transporters that are involved in drug absorption,

* Corresponding author. Faculty of Pharmaceutical Sciences, Josai University, Keyakidai 1-1, Sakado, Saitama 350-0295, Japan. Tel.: +81 49
2717269.
E-mail address: [email protected] (K. Sunaga).
Peer review under responsibility of Shenyang Pharmaceutical University.
1
Present address: Development Division, Ryusendo Co., Ltd., Nishiikebukuro 1-5-3, Toshimaku, Tokyo, Japan.
2
Present address: Site Support Institute Co., Ltd., Minatoku, Shibaura 1-1-1, Tokyo, Japan.
Abbreviations: TJ, tomato juice; GFJ, grapefruit juice; NFP, nifedipine; MDZ, midazolam; AUC, area under the concentration–time curve;
CYP, cytochrome P450; 9-oxo-ODA, 9-oxo-10,12-octadecadienoic acid; 13-oxo-ODA, 13-oxo-9,11-octadecadenoic acid.
http://dx.doi.org/10.1016/j.ajps.2017.05.004
1818-0876/© 2017 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 asian journal of pharmaceutical sciences 12 (2017) 464–469 465

distribution, metabolism, and excretion. Pharmacodynamic in- 2.3. Animal experiments

teractions involve the pharmacological effects of a drug or the
physiologic effect of a dietary constituent [1]. Eight-week-old (180–200 g) male Wistar rats (Sankyo Labo Service
Foods and beverages that inhibit cytochrome P450 (CYP) drug Co., Tokyo, Japan) were given free access to water and a normal
metabolism enzymes can elevate the blood concentrations of laboratory diet (MF, Oriental Yeast Co., Tokyo, Japan). All animals
co-administered drugs, resulting in food–drug interactions with were acclimatized for 1 week and maintained in a room with
potentially adverse effects [2–4]. In vitro screening assays that controlled temperature (23 ± 3 °C), humidity (55 ± 10%), and a
have evaluated various food and beverages, including beer, red 12 h day/night cycle. All animal studies were performed in
wine, black and herbal teas, garlic, spices, mace, nutmeg, fruits, accordance with the “Standards Relating to the Care and Man-
and fruit juices, have shown the ability of these to inhibit agement of Experimental Animals” (Notice No. 6 of the Office
enzyme-mediated drug metabolism [5–10]. In addition, several of Prime Minister, dated March 27, 1980) and the guidelines of
fruit juices have been reported to cause pharmacokinetic food– the Institutional Animal Care and Use Committee at the Josai
drug interactions in vivo, including grapefruit (GFJ) [11–14], University Life Science Center.
orange [12], star fruit [15], pomelo [16], cranberry [17], and pome-
granate juice [18]. 2.4. Pharmacokinetic studies
Recently, we reported that tomato juice (TJ) extract con-
tains potent mechanism-based inhibitor(s) of CYP3A4 similar Rats were fasted overnight before experiments. For pharma-
to GFJ [19]. However, whether TJ can alter the pharmacoki- cokinetic studies, rats were anesthetized with 20% urethane
netic profile of CYP3A-substrate drugs remains unknown. (1 g/kg body weight, intraperitoneally) 60 min after treat-
TJ is a very popular beverage; epidemiological studies ment with peroral administration (p.o.) of TJ, GFJ, or water. NFP
have indicated that high consumption of tomato products is (3 mg/kg/ml) or MDZ (20 mg/kg/ml) were then administered
related to the reduced risk of prostate cancer [20,21]. Lycopene, 30 min later via the duodenum or femoral vein. Blood samples
a major ingredient in tomato, shows promising anticancer (0.2 ml) were collected via the jugular vein at 2.5, 5, 10, 15, 30,
effects, including antioxidant activity, inhibition of cell cycle 60, 90, 120, 180, and 240 min for intraduodenal administra-
progression, apoptosis induction, increased gap-junctional tion (i.d.) or at 1, 5, 10, 30, 60, 90, 120, 180, and 240 min for
cell communication, inhibition of insulin-like growth factor I intravenous administration (i.v.). Samples were immediately
signal transduction, and inhibition of androgen activation and centrifuged at 15,000 rpm (4 °C) for 5 min, and plasma was sepa-
signaling [22,23]. Furthermore, it has recently been reported rated. Plasma samples were stored at −40 °C until analysis.
that a conjugated linoleic acid (CLA) derivative, 9-oxo-10,12-
octadecadienoic acid (9-oxo-ODA) [24], which is present in 2.5. HPLC analysis of NFP and MDZ
fresh tomato fruit, and 13-oxo-9,11-octadecadenoic acid
(13-oxo-ODA) [25], which is an isomer of 9-oxo-ODA and present A 25-µl aliquot of each thawed plasma sample was trans-
in only TJ but not in fresh tomato fruit, both serve as PPARa ferred into a new tube with 50 µl acetonitrile containing internal
agonists. These reports suggest that 13-oxo-ODA is a more standard (100 ng methylparaben for NFP, 100 ng diazepam for
potent PPARa agonist than 9-oxo-ODA, and may improve MDZ). After vigorous mixing, samples were centrifuged at
obesity-induced dyslipidemia and hepatic steatosis. 15,000 × g for 10 min at 4 °C. The supernatant (20 µl) was di-
To date, no studies have investigated whether TJ can cause rectly injected into the HPLC system, which consisted of a
adverse food–drug interactions in vivo. In this study, we evalu- PU2089 pump, UV2075 UV absorbance detector, an AS2057 auto
ated the potential of TJ to influence the disposition of drugs injector, and a ChromNAV system controller (JASCO). For NFP,
that are metabolized by CYP3A4, such as nifedipine (NFP) and the HPLC conditions included a Myghtysil RP-18GP column
midazolam (MDZ). (5 µm, 4.6 mm × 250 mm; Kanto Chemical Co., Tokyo, Japan) con-
nected to a precolumn (5 µm, 2 × 5 mm; Kanto Chemical Co,
Tokyo, Japan), and eluted at a flow rate of 1.0 ml/min with a
2. Materials and methods mobile phase of acetonitrile: 10 mM sodium phosphate [pH 6.1;
45:55 (v/v)]. Detection of NFP was performed by analyzing
2.1. Materials the UV absorbance at 236 nm. The retention time was 12.5 min
for NFP and 5.4 min for methylparaben. For MDZ, the HPLC
NFP was purchased from Sigma-Aldrich (MO, USA). MDZ was conditions included a Myghtysil RP-18GP column (5 µm,
purchased from Wako Pure Chemical Ind., Ltd. (Osaka, Japan). 4.6 mm × 150 mm; Kanto Chemical Co., Tokyo, Japan) con-
Acetonitrile was purchased from Kanto Chemical (Tokyo, Japan) nected to a precolumn (5 µm, 2 mm × 5 mm; Kanto Chemical
and was used for high performance liquid chromatography. All Co, Tokyo, Japan), and eluted at a flow rate of 1.0 ml/min with
other reagents were of analytical grade. a mobile phase of acetonitrile:10 mM sodium acetate [pH 4.7;
45:55 (v/v)]. Detection was performed by analyzing the UV ab-
2.2. Test samples sorbance at 220 nm. The retention time was 6.5 min for MDZ
and 9.4 min for diazepam.
Additive-free TJ was purchased from Ito En Ltd. (Tokyo, Japan).
Grapefruits (Citrus paradisi Macf.) were obtained from local com- 2.6. Data analysis
mercial sources. Minced fresh grapefruit (without epicarp) was
homogenized with an AM-8 homogenizer (Nihon Seiki Co., Ltd., The blood concentration–time profile data (0–4 h) from each
Tokyo, Japan). rat was analyzed by a model-independent method using the
466 asian journal of pharmaceutical sciences 12 (2017) 464–469

MULTI computer program [26]. We obtained following param- method. In addition, we used 5 ml/kg dose of TJ, GFJ, and water
eters: peak time (T max ), maximum concentration (C max ), in this study. This dose was appropriate as it corresponds to
elimination rate constant (kel), area under the curve (AUC), mean an intake of 300–400 ml for persons weighing 60–80 kg.
residence time from zero to infinity (MRT), elimination half-
life (t1/2), total clearance (CLtot), and volume of distribution (Vd). 3.2. Effects of GFJ on intraduodenally administered NFP
The oral bioavailability (F) was calculated using AUCp.o./AUCi.v.. and MDZ pharmacokinetics
Statistical differences between the treatment and control groups
were evaluated using Dunnett’s test; a P value of <0.05 was con- When GFJ (5 ml/kg) was orally administered 90 min before
sidered significant. intraduodenal administration of NFP (3 mg/kg) or MDZ
(20 mg/kg), the area under the concentration–time curve (AUC)
of NFP (Fig. 1A and Table 1) and MDZ (Fig. 2A and Table 2) in-
creased by 30.3% and 58.1%, respectively, compared with that
3. Results and discussion
of water. Consequently, GFJ significantly increased both the
blood concentrations and AUC of intraduodenally adminis-
We have previously found that TJ extract contains potent tered NFP and MDZ. These findings were identical to those of
mechanism-based inhibitor(s) of CYP3A4 similar to those of previous reports [14,30].
GFJ [19]. This study investigated whether TJ affects CYP3A4-
substrate drug disposition in vivo. We employed two CYP3A4 3.3. Effects of TJ on intraduodenally administered NFP
substrate drugs NFP and MDZ to judge whether TJ influenced and MDZ pharmacokinetics
the pharmacokinetics of CYP3A4-substrate drugs compared
with that of water, and the results were compared to those In contrast, TJ increased the MDZ blood concentrations and the
of GFJ. AUC by 73.0% (Fig. 2B and Table 4) compared with water but
did not influence NFP blood concentration and parameters
3.1. Dosage of NFP, MDZ, and test samples (Fig. 1B and Table 3). These results demonstrate that TJ has the
potential to influence the pharmacokinetics of some CYP3A4-
The doses of NFP [14,27] and MDZ [28,29] are similar to the doses substrate drugs in rats, similar to the findings for GFJ.
used in previous studies on in vivo pharmacokinetics in rats. However, TJ did not influence the pharmacokinetics of NFP
These doses can sufficiently detect plasma drugs by the HPLC and MDZ to the same extent as GFJ did. The reasons for this

A C

Fig. 1 – Plasma concentration–time profiles of rats treated with 3 mg/kg nifedipine 90 min after a single exposure to TJ, GFJ,
or water (5 ml/kg, p.o.). A and B, intraduodenal administration; C, intravenous administration. Each point and bar
represents the mean and SD of five or six rats. *P < 0.05 compared to control values.
 asian journal of pharmaceutical sciences 12 (2017) 464–469 467

Table 1 – Pharmacokinetic parameters of Table 2 – Pharmacokinetic parameters of

intraduodenally and intravenously administered NFP intraduodenally and intravenously administered MDZ
after pre-treatment GFJ or water. after pre-treatment with GFJ or water.
I.D. administration I.V. administration I.D. administration I.V. administration
Control GFJ Control GFJ Control GFJ Control GFJ
Tmax (h) 0.17 ± 0.02 0.20 ± 0.04 - - Tmax (h) 0.49 ± 0.21 0.50 ± 0.00 - -
Cmax (µg/ml) 5.30 ± 1.14 5.92 ± 1.48 - - Cmax (µg/ml) 1.66 ± 0.64 2.53 ± 1.04 - -
Kel (h−1) 0.50 ± 0.11 0.42 ± 0.20 0.57 ± 0.25 0.58 ± 0.07 Kel (h−1) 0.44 ± 0.23 0.32 ± 0.14 0.53 ± 0.29 0.44 ± 0.07
AUC (µg/ml · h) 6.87 ± 1.61 8.95 ± 1.65a 11.6 ± 0.76 13.7 ± 1.59 AUC (µg/ml·h) 2.72 ± 0.79 4.30 ± 1.25a 10.5 ± 2.80 13.5 ± 1.31a
MRT (h) 1.27 ± 0.07 1.37 ± 0.36 0.91 ± 0.18 0.76 ± 0.22 MRT (h) 1.34 ± 0.28 1.56 ± 0.08 0.85 ± 0.13 0.99 ± 0.09
t1/2 (h) 1.44 ± 0.31 1.95 ± 1.05 1.35 ± 0.58 1.21 ± 0.16 t1/2 (h) 2.35 ± 1.41 2.13 ± 0.64 1.52 ± 0.74 1.61 ± 0.27
CLtot (ml/h/kg) 0.12 ± 0.02 0.09 ± 0.02 0.07 ± 0.02 0.06 ± 0.02 CLtot (ml/h/kg) 0.20 ± 0.08 0.15 ± 0.07 0.09 ± 0.02 0.07 ± 0.007a
Vd (ml/kg) 0.21 ± 0.02 0.21 ± 0.04 0.09 ± 0.20 0.08 ± 0.02 Vd (ml/kg) 0.61 ± 0.36 0.61 ± 0.31 0.13 ± 0.25 0.03 ± 0.009
F (%) 59.2 65.3 ― ― F (%) 26.0 31.8 ― ―
Data represent means ± SD (n = 5–6). Data represent means ± SD (n = 5–6).
a
P < 0.05 compared to control values. a
P < 0.05 compared to control values.

are not clear; however, differences in oral bioavailability of CYP3A4 and CYP2C9 in male beagle dogs, but not in rats,
(Tables 1, 2, and 4) of NFP (59.2%) and MDZ (26.0%–26.1%) may indicating that the rat may not be an appropriate model [32].
be a contributing factor. It has previously been reported that In this study, these factors may have contributed to our find-
single-strength GFJ significantly increases the plasma concen- ings that TJ did not influence NFP disposition. However, more
trations of NFP in rats [14]. On the other hand, there is a report research should be warranted.
that while concentrated GFJ (2 × concentrations) significantly The clinical significance of CYP3A4 inhibition by TJ is not
increases NFP bioavailability in rats, regular strength GFJ has well understood. In one study in which TJ was used as a
no significant effect on NFP bioavailability [31]. Furthermore, ‘vehicle’, it was reported that TJ does not influence the phar-
it has been reported that pre-dosing with the GFJ constituent macokinetics of the proton pump inhibitor lansoprazole [33].
bergamottin increases the plasma level of diazepam, a substrate However, this is likely due to the fact that the study was not

A C

B D

Fig. 2 – Plasma concentration–time profiles of rats treated with 20 mg/kg midazolam 90 min after a single exposure to TJ,
GFJ, or water (5 ml/kg, p.o.). A and B, intraduodenal administration; C and D, intravenous administration. Each point and bar
represents the mean and SD of five or six rats. **P < 0.01, *P < 0.05 compared to control values.
468 asian journal of pharmaceutical sciences 12 (2017) 464–469

only intestinal but also hepatic drug metabolism). On the other

Table 3 – Pharmacokinetic parameters of
hand, several studies have suggested that GFJ selectively in-
intraduodenally administered NFP after pre-treatment
with TJ or water. hibits intestinal CYP3A4, as opposed to hepatic CYP3A4 [34–36].
Thus, GFJ reportedly did not alter the pharmacokinetics of
I.D. administration
CYP3A4 substrates administered intravenously [30,37], and little
Control TJ change in the elimination half-life was observed when the drugs
Tmax (h) 0.17 ± 0.04 0.17 ± 0.04 were administered orally [37,38]. On the other hand, it has been
Cmax (µg/ml) 7.21 ± 1.65 6.97 ± 0.83 reported that the consumption of one glass of double-strength
Kel (h−1) 0.62 ± 0.14 0.59 ± 0.07 GFJ three times a day for 3 d significantly increases the AUC,
AUC (µg/ml·h) 6.64 ± 1.68 6.72 ± 0.92
Cmax, and t1/2 of MDZ and reduces the erythromycin breath test
MRT (h) 0.95 ± 0.15 0.99 ± 0.07
value [39]. These observations indicate that high doses of GFJ
t1/2 (h) 1.16 ± 0.23 1.18 ± 0.13
CLtot (ml/h/kg) 0.15 ± 0.04 0.14 ± 0.02 may inhibit both intestinal and hepatic CYP3A4 in vivo. In this
Vd (ml/kg) 0.17 ± 0.02 0.17 ± 0.02 study, appropriate experimental techniques and selection of
Data represent means ± SD (n = 5–6).
MDZ as CYP3A substrate drug may have obtained high preci-
sion results. Further investigation is required to clarify whether
GFJ and TJ influence the liver drug-metabolizing enzymes.

Table 4 – Pharmacokinetic parameters of

intraduodenally and intravenously administered MDZ
after pre-treatment with TJ or water.
4. Conclusions
I.D. administration I.V. administration
TJ increased MDZ blood concentrations and the AUC after
Control TJ Control TJ
intraduodenal MDZ administration similar to GFJ. Although it
Tmax (h) 0.43 ± 0.13 0.40 ± 0.34 - - remains unclear why TJ did not influence NFP disposition in
Cmax (µg/ml) 1.70 ± 0.67 2.76 ± 0.96 - - rats, it cannot be denied that TJ influences the pharmacoki-
Kel (h−1) 0.46 ± 0.07 0.38 ± 0.34 0.53 ± 0.29 0.56 ± 0.11
netics of other CYP3A4 substrates in humans. In future studies,
AUC (µg/ml·h) 2.74 ± 1.05 4.74 ± 0.29a 10.5 ± 2.80 12.8 ± 1.21
MRT (h) 1.44 ± 0.18 1.35 ± 0.42 0.85 ± 0.13 0.98 ± 0.04
factors underlying the variability of TJ in influencing the phar-
t1/2 (h) 2.56 ± 0.34 1.86 ± 1.99 1.52 ± 0.74 1.29 ± 0.34 macokinetics of CYP3A4 substrates should be investigated,
CLtot (ml/h/kg) 0.21 ± 0.04 0.17 ± 0.11 0.09 ± 0.02 0.07 ± 0.009 particularly for humans in order to perform inter-species
Vd (ml/kg) 0.68 ± 0.11 0.42 ± 0.49 0.13 ± 0.2 0.09 ± 0.004 comparisons.
F (%) 26.1 37.0 ― ―
Data represent means ± SD (n = 5–6).
a
P < 0.01 compared to control values.
Acknowledgements

The authors would like to thank Enago (www.enago.jp) for the

specifically designed to evaluate the inhibitory effect of TJ
English language review.
on CYP3A. In addition, lansoprazole is not an established
CYP3A probe substrate, and the tomato juice product used was
not characterized prior to use. The possibility of a food–drug
interaction between tomato juice and appropriate CYP3A Conflicts of interest
substrates needs further examination in clinical studies.
The authors declare that there is no conflicts of interest.
3.4. Effects of TJ and GFJ on intravenously administered
NFP and MDZ pharmacokinetics
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