apparently occurs in 3–10% of Caucasians and is inherited as an correlates with a higher risk of relapse in patients with breast autosomal recessive trait. In affected individuals, the CYP2D6-cancer treated with tamoxifen, an anticancer drug that relies on its dependent oxidations of debrisoquin and other drugs (Table 4–2; CYP2D6-dependent metabolic activation to endoxifen for its effi-Figure 4–6) are impaired. These defects in oxidative drug metabo-cacy. More recently, however, another polymorphic genotype has lism are probably co-inherited. The precise molecular basis for the been reported that results in ultrarapid metabolism of relevant defect appears to be faulty expression of the P450 protein due to drugs due to the presence of CYP2D6 allelic variants with up to either defective mRNA splicing or protein folding, resulting in 13 gene copies in tandem. This ultrarapid metabolizer (UM) gen-little or no isoform-catalyzed drug metabolism and thereby con-otype is most common in Ethiopians and Saudi Arabians, populaferring a poor metabolizer (PM) phenotype. This PM phenotype tions that display it in up to one third of individuals. As a result, –2.0 –1.0 0 1.0 2.0 Log10 metabolic ratio
FIGURE 4–6 Genetic polymorphism in debrisoquin 4-hydroxylation by CYP2D6 in a Caucasian population. The semilog frequency distribution histogram of the metabolic ratio (MR; defined as percent of dose excreted as unchanged debrisoquin divided by the percent of dose excreted as 4-hydroxydebrisoquin metabolite) in the 8-hour urine collected after oral ingestion of 12.8 mg debrisoquin sulfate (equivalent to 10 mg free debrisoquin base). Individuals with MR values >12.6 were phenotyped as poor metabolizers (PM, red bars), and those with MR values <12.6 but >0.2 were designated as extensive metabolizers (EM, blue bars). Those with MR values <0.2were designated as ultrarapid metabolizers (URM, green bars) based on the MR values (0.01–0.1) of individuals with documented multiple copies of CYP2D6 allelic variants resulting from inherited amplification of this gene. (Data from Woolhouse et al: Debrisoquin hydroxylation polymorphism among Ghanians and Caucasians. Clin Pharmacol Ther 1979;26:584.) these subjects require twofold to threefold higher daily doses of nortriptyline (an antidepressant and a CYP2D6 substrate) to achieve therapeutic plasma levels. The poor responsiveness to antidepressant therapy of the UM phenotype also clinically correlates with a higher incidence of suicides relative to that of deaths due to natural causes in this patient population. Conversely, in these UM populations, the prodrug codeine (another CYP2D6 substrate) is metabolized much faster to morphine, often resulting in undesirable adverse effects of morphine, such as abdominal pain. Indeed, intake of high doses of codeine by a mother of the ultrarapid metabolizer type was held responsible for the morphine-induced death of her breast-fed infant.