Genetic Factors Affecting Serum Drug Concentrations

There are wide variations in a patient's response to drug therapy. One patient may demonstrate desirable pharmacological effect after administration of a particular dose of a drug whereas another patient may show only subtle effects. Although such variability may be related to renal disease or liver disease or due to drug-drug interactions, alteration of drug-metabolizing capacity caused by hereditary enzymatic deficiency or over-expression may also lead to an altered response of a patient to a drug. As early as in 1964, Kurt et al. (36) reported that phenytoin toxicity in a patient receiving the usual dose of phenytoin was probably related to a rare genetic deficiency in phenytoin hydroxylation.

Although over 15 different enzymes have been identified in the liver, in practice the cytochrome P450 isoenzymes that mediate the oxidative metabolism of many drugs include CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. These enzymes show marked variations in different people. Some of these enzymes also exhibit genetic polymorphism (CYP2C19, CYP2D6), and a subset of the population may be deficient in enzyme activity (poor metabolizer). Therefore, if a drug is administered to a patient who is a poor metabolizer, drug toxicity may be observed even with a standard dose of the drug. Phenotyping procedures commonly involve administration of a probe drug and calculation of the urine or plasma metabolic ratio. CYP3A4 is the most abundant hepatic oxidative enzyme in the liver, and it accounts for almost 30% of the cytochrome P450 enzyme system (37). This isoenzyme is also present in significant amounts in the epithelium of the gut, and orally administered drugs, which are substrate of CYP3A4, may undergo significant metabolism before entering circulation. CYP3A4 exhibits significant inter-individual variation that may be as high as 20-fold. The knowledge that a drug is metabolized by a certain cytochrome P450 enzyme is indicative that this drug can competitively inhibit the metabolism of other drugs, which are also substrates of this enzyme. Often the cytochrome P450 can be induced by another drug or a herbal supplement, such a St. John's wort resulting in a lower plasma concentration of a drug because of increased metabolism of the drug. Drug interactions with St. John's wort are discussed in detail in Chapter 13.

Pharmacogenomics approach to personalized medicine is based on the utilization of genetic information data in pharmacotherapy and drug delivery thus ensuring better drug efficacy and safety in patient management. Currently, the concept of personalized medicine and pharmacogenetics are likely to improve the areas of pharmacokinetics and pharmacodynamics because genetic polymorphisms have already been detected and analyzed in genes coding drug-metabolizing enzymes, transporters as well as well as target receptors. The potential of applying genotyping and haplotype analysis in future medical care could eventually lead to pharmacotyping referring to individualized drug delivery profiling based on genetic information (38). The United States Federal Drug Administration (FDA) has granted market approval for the first pharmacogenetic testing using a DNA microarray, the AmpliChip CYP450, which genotypes cytochrome P450 (CYP2D6 and CYP2C19). The test uses software to predict phenotypes and tests for 27 CYP2D6 alleles (39). Pharmacogenomics issues are discussed in Chapter 11.

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