Teerthanker Mahaveer University

Moradabad Uttar Pradesh

Assignment
On
Pharmacokinetic Drug Interaction

Submitted by Submitted To
Samad Khan Dr KK Sharma
TPH1912023 Professor
Pharm D TMCOP
 Pharmacokinetic
Pharmacokinetics is a branch of pharmacology that deals with the study of how
a drug or medication is absorbed, distributed, metabolized, and excreted by the
human body. It essentially focuses on what the body does to a drug after it has
been administered. This information is crucial in determining the proper dosing
and administration of medications, as well as understanding their effects on the
body.
Drug-drug interactions (DDIs) are one of the commonest causes of medication
error in developed countries, particularly in the elderly due to poly-therapy, with
a prevalence of 20-40%. In particular, poly-therapy increases the complexity of
therapeutic management and thereby the risk of clinically important DDIs,
which can both induce the development of adverse drug reactions or reduce the
clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic
and pharmacodynamic.

INTRODUCTION

Drug-drug interactions (DDIs) are one of the commonest causes of ADRs and
we reported that these manifestations are commons in the elderly due to poly-
therapy. In fact, poly-therapy increases the complexity of therapeutic
management and thereby the risk of clinically relevant drug interactions, which
can induce the development of ADRs, and both reduce, or increase the clinical
efficacy.

Poly-therapy may determine the “prescribing cascade,” which occurs when an

ADR is misunderstood and new potentially unnecessary drugs are administered;
therefore the patient is at risk to develop further ADRs.

DDI can be classify into two main groups:

 Pharmacokinetic: Involves absorption, distribution, metabolism and

excretion, all of them being associated with both treatment failure or
toxicity;
 Pharmacodynamic: may be divided into three subgroups: direct effect at
receptor function, interference with a biological or physiological control
process and additive/opposed pharmacological effect.
DISTRIBUTION

Usually, drugs are transported through a binding to plasma and tissues proteins.
Of the many plasma proteins interacting with drugs, the most important are
albumin, α1-acid glycoprotein, and lipoproteins. Acidic drugs are usually bound
more extensively to albumin, while basic drugs are usually bound more
extensively to α1-acid glycoprotein, lipoproteins, or both. Only unbound drug is
available for passive diffusion to extravascular or tissue sites and typically
determines drug concentration at the active site and thus its efficacy. Albumin
represents the most prominent protein in plasma, it is synthesized in the liver
and distributed in both plasma and extracellular fluids of skin, muscles and
various tissues. Intestinal fluid albumin concentration is about 60% of that in
the plasma. Since albumin has five binding sites (i.e., for warfarin,
benzodiazepines, digoxin, bilirubin and tomoxifen), the main characterized are
the site I and II

Metabolism

The CYP enzyme family plays a dominant role in the biotransformation of a

wide number of drugs. In man, there are about 30 CYP isoforms, which are
responsible for drug metabolism and these belong to families 1-4, but only 6 out
of 30 isoforms belonging to families CYP1, 2 and 3 (i.e., CYP1A2, 3A4, 2C9,
2C19, 2D6 and 2E1) are mainly involved in the hepatic drug metabolism.

The broad range of drugs that undergo CYP mediated oxidative

biotransformation is responsible for the large number of clinically significant
drug interactions during multiple drug therapy. Many DDIs are related to the
inhibition or induction of CYP enzymes.

DDIs during excretion

The organs and vehicles deputy at the drugs excretion (elimination) are kidneys,
liver, lungs, feces, sweat, saliva, milk. The excretion through saliva, sweat and
lungs (for volatile drugs) and milk has little quantitative significance, but the
milk is important when the drugs can reach the baby during lactation.

Drugs are excreted mainly through:

  Renal tubular excretion (glomerular filtration, tubular reabsorption and
active tubular secretion)
 Biliary excretion.

The drugs elimination from the body can undergo many interactions being
excreted by another drug in this organ from, which it is excreted.

The kidney is the organ responsible for the elimination of drugs and their
metabolites. The interaction may occur for a mechanism of competition at the
level of active tubular secretion, where two or more drugs use the same
transport system. An example is given by NSAIDs that determine the
appearance of toxic effects caused by methotrexate when the renal excretion of
the anti-proliferative drug is blocked.

It was also demonstrated that amoxicillin decreased the renal clearance of

methotrexate.

Probenecid, a potent inhibitor of the anionic pathway of renal tubular secretion,

increases of 2.5 times the area under the AUC of oseltamivir.

However, this competition between drugs can be exploited for therapeutic

purposes. For example, probenecid can increase the serum concentration of
penicillins and cephalosporins, delaying their renal excretion and thus saving in
terms of dosage. In fact, probenecid acts by competitively inhibiting an organic
anion transporter in renal tubules, thus increasing plasma concentrations of
other transporter substrates, while reducing their excretion.

Several drugs are able to interfere with tubular transport. In particular,

cimetidine, an H2 receptor inhibitor, may influence the tubular secretion of
different molecules. Its effect on the influx and the efflux of organic cations
through human organic cation transporter ([hOCT1 and hOCT2] and human
multidrug and toxin extrusion [hMATE1 and hMATE2-K]) could modify other
drug serum concentration despite a normal renal function.

Moreover, in vitro study documented that PPIs (i.e., omeprazole, pantoprazole,

lansoprazole, rabeprazole, and tenatoprazole) are potent hOCT-inhibitors and
could modulate the transport of metformin. However, the clinical relevance of
this DDIs may be clarify. The interactions can also occur during tubular
reabsorption. Many drugs, when they are in an ionized form in the urine, pass
by diffusion in tubular cells. The changes in urinary pH, pharmacologically
induced, influence the state of ionization of certain drugs and may therefore
affect the re-absorption from the renal tubule.

In particular, if the pH of the urine is alkaline the absorption of acidic drugs is

reduced, while, in the presence of an acidic pH, basic drug absorption is
reduced.

The changes in urinary pH, however, assume practical importance only if the
pKa of the drug, i.e., the pH at which 50% of the molecules in solution is
present in ionized form, is between 7.5 and 10.5 for the bases, and between 3.0
and 7.5 for acids.

In fact, the pKa values can cause appreciable changes in the degree of
dissociation of the drug. Compounds such as ammonium chloride,
tromethamine and diuretics, being able to change urine pH, may affect the
excretion of several acidic and basic drugs, and this interaction may be used to
facilitate the removal of drugs from the body. On the contrary, the interaction
between diuretics and lithium salts can still have negative effects on the patient.

Lithium is a monovalent cation whose excretion is influenced by changes of

serum sodium. Therefore, a high excretion of sodium induced by chronic
treatment with some diuretics such as thiazides, may increase lithium re-
absorption, causing serious toxic effects from relative over dosage.

Some acidic and basic drugs with the high degree of ionization are transferred
through the epithelium of the renal tubule by active transport. The speed
transfer of molecules depends on the availability of the transporter, a protein
that allows the transfer through the cellular membranes. Therefore, when two
drugs are substrate of the same transmembrane transporter they can complete
each other, up to the saturation of transporter capacity. At that time, the rate of
elimination approaches to a zero order (saturable) process.

Strategy to prevent pharmacokinetic DDI

The Summary of Product Characteristics (SPCs) represents the primary source

of information about DDIs for health care professionals. Unfortunately, DDI
cannot be listed exhaustively. consequently the information on potential DDIs
may be insufficiently described, due to the limited space in the SPC.

In fact, in an Italian study cross-sectional study, was found that the 3.0% of PPI
users were exposed to potential DDI within 1 year of follow-up, according to
the risk described in the Italian SPCs of PPIs, but this proportion was three-fold
higher (9.0%) when information about DDI risk with PPIs, reported on
Drugdex, was considered.

Therefore, reports on DDI that consider different sources updated on the basis
of current evidence from the literature should be useful to evaluate a possible
risk of DDI particularly in elderly patients with poly-therapy.

Moreover, even if not always available and feasible, the adoption of therapeutic
drug monitoring protocols in the above reported patients (i.e., elderly people
with comorbidities treated with multiple drugs) should be considered an
important instrument to decrease the occurrence and magnitude of DDIs that
could induce either an increase in health costs for the Health system and a legal
responsibility for the clinicians.

Therefore, we hope that the National Health System plan a strategy intervention
to keep physicians adequately aware of potential DDI, with particular regard to
widely used medications.

However, in this time, reports on DDIs that consider different sources updated
on the basis of current evidence from the literature should be useful to evaluate
a possible risk of DDI particularly in elderly patients with poly-therapy.

Previously it has been reported that genetic polymorphism of CYP enzymes

played a significant role in the clinical effects of drug treatment as well as in the
development of DDIs.

Here are some examples of drug interactions:

1. Grapefruit Juice and Medications: Grapefruit juice can inhibit the

activity of certain enzymes in the liver, which affects the metabolism of
many drugs. This can result in increased blood levels of some
medications, leading to potentially toxic effects. Common drugs affected
include statins, certain blood pressure medications, and some psychiatric
drugs.
2. Warfarin and Vitamin K: Warfarin is a blood thinner used to prevent
blood clotting. Vitamin K antagonizes its effects, so consuming foods
high in vitamin K (e.g., leafy greens) can interfere with the drug's
effectiveness.
3. Antibiotics and Birth Control Pills: Some antibiotics, like rifampin and
certain types of penicillin, can reduce the effectiveness of birth control
pills. This can increase the risk of unintended pregnancy.
4. MAOIs and Foods High in Tyramine: Monoamine oxidase inhibitors
(MAOIs), a class of antidepressants, can interact with foods high in
tyramine, like aged cheeses, certain wines, and cured meats, potentially
leading to a dangerous increase in blood pressure.
5. NSAIDs and Antiplatelet Drugs: Non-steroidal anti-inflammatory drugs
(NSAIDs), such as ibuprofen, can interfere with the antiplatelet effects of
drugs like aspirin, increasing the risk of blood clots and cardiovascular
events.
6. Alcohol and Sedatives: Combining alcohol with sedative medications
like benzodiazepines can lead to extreme sedation and respiratory
depression, which can be life-threatening.
7. Lithium and Diuretics: Diuretics can decrease the excretion of lithium,
a medication used to treat bipolar disorder, leading to increased levels of
lithium in the blood, potentially causing toxicity.