Pharmacogenetic Phenotypes

Candidate genes for therapeutic and adverse response can be divided into three categories: pharmacokinetic, receptor/target, and disease-modifying.

PHARMACOKINETICS Germline variability in genes that encode factors that determine the pharmacokinetics of a drug, in particular enzymes and transporters, affect drug concentrations and are therefore major determinants of therapeutic and adverse drug response (Table 4-2). Multiple enzymes and transporters may affect the pharmacokinetics of a given drug. Several polymorphisms in drug metabolizing enzymes are monogenic phenotypic trait variations and thus are referenced using their phenotypic designations (e.g., slow vs. fast acetylation, extensive vs. poor metabolizers of debrisoquine or sparteine) rather than using genotypic designations that reference the gene that is the target of polymorphisms in each case (e.g., NAT2 and CYP2D6, respectively). A large number of medications (-15-25% of all medicines in use) are known substrates for CYP2D6 (Table 4-2). The molecular and phenotypic characterization of multiple racial and ethnic groups has shown that seven variant alleles account for >90% of the "poor metabolizer" low-activity CYP2D6 alleles in most racial groups, that the frequency of variant alleles varies with geographic origin, and that a small percentage of individuals carry stable duplications of CYP2D6, with "ultrarapid" metabolizers having up to 13 copies of the active gene. Phenotypic consequences of the deficient CYP2D6 phenotype include increased risk of toxicity of antidepressants or antipsychotics (catabolized by the enzyme), and lack of analgesic effect of codeine (anabolized by the enzyme); conversely, the ultra-rapid phenotype is associated with extremely rapid clearance and thus decreased efficacy of antidepressants.

CYP2C19, historically termed mephenytoin hydroxylase, displays pharmacogenetic variability, with just a few SNPs accounting for the majority of the deficient, poor metabolizer phenotype. The deficient phenotype is much more common in Chinese and Japanese populations. Several proton pump inhibitors (e.g., omeprazole and lansoprazole) are inactivated by CYP2C19. Thus, the deficient patients have higher exposure to active parent drug, a greater pharmacodynamic effect (higher gastric pH), and a higher probability of ulcer cure than heterozygotes or homozygous wild-type individuals.

The anticoagulant warfarin is catabolized by CYP2C9. Inactivating polymorphisms in CYP2C9 are common—with 2-10% of most populations being homozygous for low-activity variants—and are associated with lower warfarin clearance, lower dose requirements, and a higher risk of bleeding complications.

Thiopurine methyltransferase (TPMT) methylates thiopurines such as mercaptopurine (an antileukemic drug that is also the product of azathioprine metabolism). One in 300 individuals is homozygous deficient, 10% are heterozygotes, and about 90% are homozygous for wild-type TPMT alleles. Three SNPs account for over 90% of the inactivating alleles. Because methylation of mercap-topurine competes with activation of the drug to thioguanine nucleotides, the concentration of the active (but also toxic) thioguanine metabolites is inversely related to TPMT activity and directly related to the probability of pharmacologic effects. Dose reductions (from that appropriate for the "average" population) may be required to avoid myelosuppression in 100% of homozygous deficient patients, 35% of heterozygotes, and only 7-8% of those with homozygous wild-type activity. Mercaptopurine has a narrow therapeutic range, and dosing by trial and error can place patients at higher risk of toxic-ity; thus, prospective adjustment of thiopurine doses based on TPMT genotype has been proposed, both for leukemia and for nonmalignant diseases such as Crohn's disease and transplant rejection.

PHARMACOGENETICS AND DRUG TARGETS Gene products that are direct drug targets have important roles in pharmacogenetics. Whereas highly penetrant genetic variants with profound functional consequences may cause disease phenotypes that confer negative selective pressure, more subtle variations in the same genes can persist in the population without causing disease but nonetheless affecting drug response. Methylenetetrahydrofolate reductase (MTHFR), the target of several antifolate drugs, interacts with folate-dependent one-carbon synthesis reactions. Complete inactiva-tion via rare point mutations in MTHFR causes severe mental retardation and premature cardiovascular disease. Whereas rare variants in MTHFR may result in the severe phenotype, the C677T SNP causes an amino acid substitution that is maintained in the population at a high frequency. The T variant is associated with modestly lower MTHFR activity (-30% less than the 677C allele) and modest, but significantly elevated, plasma homocysteine concentrations This polymorphism does not alter

Examples of Genetic Polymorphisms Influencing Drug Response

Gene Product (Gene)

Drugs

Responses Affected

Drug metabolizing enzymes CYP2C9

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