Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele

Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of man y drugs, Several alleles for the CYP2C9 gene have been reported. Individual s homozygous for the Leu(359) variant (CYP2C9*3) have been shown to have si gnificantly lower drug clearances compared with Ile(359) (CYP2C9*1) homozyg ous individuals. A male Caucasian who participated in six bioavailability s tudies in our laboratory over a period of several years showed extremely lo w clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C 9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP 2D6 substrate). His oral clearance of phenytoin was 21% of the mean of the other 11 individuals participating in the study, and his oral clearance of glipizide, a second generation sulfonylurea structurally similar to tolbuta mide, was only 18% of the mean of the other 10 individuals. However, his or al clearance of nifedipine and chlorpheniramine did not differ from individ uals in other studies performed at our laboratories. An additional blood sa mple was obtained from this individual to determine if he possessed any of the known CYP2C9 or CYP2C19 allelic variants that would account for his poo r clearance of the CYP2C9 substrates (phenytoin and glipizide) compared wit h the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates, The res ults of the genotype testing showed that this individual was homozygous for the CYP2C9*S allele and did not possess any of the known defective CYP2C19 alleles. This study establishes that the Leu(359) mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype, Pha rmacogenetics 9:71-80 (C) 1999 Lippincott Williams & Wilkins.