Cytochrome P450, purified, soluble

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The CYP2C9 and CYP2C19 are the main isoforms for the metabolism of the antiseizure drug phenytoin and for the anticoagulant S-warfarin. Although CYP2C19 metabolizes fewer drugs than CYP2D6 does, the drugs CYP2C19 does metabolize are clinically important (Table 10.6). Deficit of CYP2C19 is found in the PM phenotype, which is only seen in 8 to 13% of Caucasians, 20 to 30% of the Asian population (11–23% of Japanese and 5–37% of Chinese), up to 20% of the black African-American population, 14 to 15% of Saudi Arabians and Ethiopians, and up to 70% of Pacific Islanders. The more common mutant allele in these individuals is CYP2C19*2, which expresses an inactive enzyme. The large interindividual variability observed in the therapeutic response to the antiseizure drug mephenytoin is attributed to CYP2C19 polymorphism, which catalyzes the p-hydroxylation of its S-stereoisomer. The R-enantiomer is N-demethylated by CYP2C8 with no difference in its metabolism between PMs and EMs.
The CYP2C9 is the primary isoform for the metabolism of the antiseizure drug phenytoin, the anticoagulant S-warfarin, and the hypoglycemic drug tolbutamide. Other clinically important drugs are listed in Table 10.6. At least six different mutant CYP2C9 alleles have been identified; of these, the two alleles primarily responsible for CYP2C9 deficiency are CYP2C9*2 and CYP2C9*3 and code for enzymes with reduced affinity for substrates. A deficiency of this isoform, however, is seen in 8 to 13% of Caucasians, 2 to 3% of African Americans, and 1% of the Asians. Individuals with the PM phenotype who possess this deficient isoform variant are ineffective in clearing S-warfarin (so much so that they may be fully anticoagulated on just 0.5 mg of warfarin per day) and in the clearance of phenytoin, which has a potentially very toxic narrow therapeutic range. On the other hand, the pro-drug losartan will be poorly activated and ineffective.