The dose and frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and elimination. These differences are determined by genetic factors as well as nongenetic variables, such as commensal gut microbiota, age, sex, liver size, liver function, circadian rhythm, body temperature, and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. The discussion that follows summarizes the most important of these variables.
Individual differences in metabolic rate depend on the nature of the drug itself. Thus, within the same population, steady-state plasma levels may reflect a 30-fold variation in the metabolism of one drug and only a twofold variation in the metabolism of another.
Genetic factors that influence enzyme levels account for some of these differences, giving rise to “genetic polymorphisms” in drug metabolism (see also Chapter 5). The first examples of drugs found to be subject to genetic polymorphisms were the muscle relaxant succinylcholine, the antituberculosis drug isoniazid, and the anticoagulant warfarin. A true genetic polymorphism is defined as the occurrence of a variant allele of a gene at a population frequency of ≥ 1%, resulting in altered expression or functional activity of the gene product, or both. Well-defined and clinically relevant genetic polymorphisms in both phase I and phase II drug-metabolizing enzymes exist that result in altered efficacy of drug therapy or adverse drug reactions (ADRs). The latter frequently necessitate dose adjustment (Table 4–4), a consideration particularly crucial for drugs with low therapeutic indices.
A. Phase I Enzyme Polymorphisms
Genetically determined defects in the phase I oxidative metabolism of several drugs have been reported (Table 4–4; see also Chapter 5). These defects are often transmitted as autosomal recessive traits and may be expressed at any one of the multiple metabolic transformations that a chemical might undergo. Human liver P450s 3A4, 2C9, 2D6, 2C19, 1A2, and 2B6 are responsible for about 75% of all clinically relevant phase I drug metabolism (Figure 4–4), and thus for about 60% of all physiologic drug biotransformation and elimination. Thus, genetic polymorphisms of these enzymes, by significantly influencing phase I drug metabolism, can alter their pharmacokinetics and the magnitude or the duration of drug response and associated events.
Three P450 genetic polymorphisms have been particularly well characterized, affording some insight into possible underlying molecular mechanisms, and are clinically noteworthy, as they require therapeutic dosage adjustment. The first is the debrisoquin-sparteine oxidation type of polymorphism, which
TABLE 4–4 Some examples of genetic polymorphisms in phase I and phase II drug metabolism.
TABLE 4–4 Some examples of genetic polymorphisms in phase I and phase II drug metabolism. (Continued) 1Observed or predictable. ADR, adverse drug reaction; EM, extensive metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer.