Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of many drugs. Several alleles for theCYP2C9gene have been reported. Individuals homozygous for the Leu359variant (CYP2C9*3) have been shown to have significantly lower drug clearances compared with Ile359(CYP2C9*1) homozygous individuals. A male Caucasian who participated in six bioavailability studies in our laboratory over a period of several years showed extremely low clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP2D6 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 tolbutamide, was only 18% of the mean of the other 10 individuals. However, his oral clearance of nifedipine and chlorpheniramine did not differ from individuals in other studies performed at our laboratories. An additional blood sample was obtained from this individual to determine if he possessed any of the knownCYP2C9orCYP2C19allelic variants that would account for his poor clearance of the CYP2C9 substrates (phenytoin and glipizide) compared with the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates. The results of the genotype testing showed that this individual was homozygous for theCYP2C9*3allele and did not possess any of the known defectiveCYP2C19alleles. This study establishes that the Leu359mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype. Pharmacogenetics 9:71–80 © 1999 Lippincott Williams & Wilkins