Pharmacogenetics Of Drugmetabolizing Enzymes

One of the most interesting and heavily researched areas of drug metabolism today is genetic polymorphism of drug-metabolizing enzymes (pharmacogenetics). As early as the late 1950s it was recognized that individuals might differ in whether they could acetylate certain drugs, such as isoniazid (see Chapter 49). In this case, the individuals studied appeared to segregate into two distinct groups, rapid acetylators and slow acetylators.

It was later discovered that this polymorphism existed in the N-acetyltransferase-2 gene and thus the NAT-2 enzyme. More important, it has become clear that slow acetylators (about 50% of the caucasian population) are more prone to adverse effects following administration of certain drugs than fast acetylators. For example, it is well established that slow acetylators receiving the antiarrhythmic drug procainamide are much more likely to develop the systemic lupus erythemato-sus-like syndrome that has been described as a characteristic and therapy-limiting event associated with this drug. In fact, this adverse event is rare in fast acetylators. Fortunately, the number of drugs that depend on NAT-2 for their primary metabolic fate is small, so this polymorphism is clinically relevant only in certain situations.

Possibly the most studied genetic polymorphism is that associated with CYP2D6. At least 17 variant alleles of this enzyme have been identified, most being associated with a deficiency in the ability to carry out CYP2D6-mediated oxidation reactions. Approximately 7% of the caucasian population is CYP2D6 deficient, whereas only 1-3% of African Americans and Asians are deficient in this enzyme. CYP2D6 is responsible for about 30% of the CYP-mediated reactions (Table 4.2) and exhibits this polymorphism. Likelihood of adverse events, such as the dyskinesias associated with certain antipsychotic agents, have been linked to this polymorphism, since individuals who are CYP2D6 deficient have a higher incidence of these side effects. To minimize adverse events and toxicity, care should be exercised when prescribing drugs that depend on CYP2D6 metabolism.

Recently, variant alleles (and thus polymorphisms) have been elucidated for most of the CYP isoforms. For example, six alleles of CYP2C9 have been discovered, and several of them profoundly affect therapy. The variant allele CYP2C9*3 occurs in fewer than 1% of the population, but affected individuals generally require doses of the anticoagulant warfarin that are 10-25% of those required by unaffected individuals. A CYP2C19 polymorphism also has been identified in 2-3% of caucasians and 20-30% of Asians. In this case, individuals who are CYP2C19 deficient are more likely to have complete ulcer healing after therapy with omeprazole (a proton pump inhibitor that reduces gastric acid) than are extensive metabolizers, a positive benefit.

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