The importance of drug pharmacokinetics to drug interactions

Genetic polymorphism

In pharmacokinetics, genetic polymorphism refers to differences between individuals' ability to metabolize drugs. More than 25 years ago it was shown that the steady-state plasma concentration of the TCA nortriptyline was related to the genetic characteristics of the patient. Thus homozygous, but not heterozygous, twins had similar blood nortriptyline concentrations. Since that time it has become clear that many of the liver enzymes concerned with drug metabolism exhibit genetic polymorphism. This may be particularly important when depressed patients receiving antidepressant therapy are also given other drugs which compete for the same hepatic enzyme.

The most important group of liver enzymes that are responsible for the oxidative metabolism of most drugs are the microsomal cytochrome P450 oxidases. There are many subtypes (termed isozymes).

Each cytochrome P450 isoenzyme is the product of a separate gene, and so far more than 200 such genes have been identified. Furthermore, a number of cytochrome P450 genes have been shown to have different alleles which have resulted from mutation. Where such a mutation exists in more than 1% of the population, the term ''genetic polymorphism'' is applied. Many of the polymorphic forms of the cytochrome P450 enzyme appear to be of minor significance in drug metabolism. Substrates and inhibitors of these isoenzymes are presented in Table 3.1.

In some individuals an isoenzyme may be absent. This is an inherited trait which can vary in incidence according to racial background.

Table 3.1. Characteristics, substrates and inhibitors of some cytochrome P450

isoenzymes

Isoenzyme Polymorphism Substrate

Inhibitor

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