Population variability of CYP2C9 activity in caucasians: Effects of genotype versus enzyme induction

Background and Aims The enzyme CYP2C9 metabolizes between 10 and 20% of all drugs. We were interested in the relative impact of rifampin induction versus genetic variability. Methods An unselected population of 106 healthy male and 37 female volunteers was studied with a 500‐mg tolbutamide test dose before and after 5 days on 450 mg rifampin. Results We identified 66.2, 15.8, 13.0, 2.88, and 0.72% carriers of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*3, and *3/*3, respectively; no carrier of *2/*2 was found. Mean total oral clearance (95% confidence intervals) before rifampin was 0.928 (0.917 ‐ 0.942), 0.779 (0.768 ‐ 0.787), 0.584 (0.576 ‐ 0.584), 0.435(0.427 ‐ 0.446), and 0.240 (0.237 ‐ 0.244) L/h in the order of genotypes given above. After rifampin induction this parameter was increased by mean factor of 1.841 (1.827 ‐ 1.854) in all groups. The effects of both, induction and genotype, were highly significant. Three allele specific clearances could be determined for the major CYP2C9 variants *1, *2, and *3 with means (standard errors) of 0.464 (0.054), 0.315 (0.050), and 0.120 (0.022) respectively. Volume of distribution strongly depended on body weight with a population mean of 8.37 L in female and 9.76 L in male. Conclusions Overall, about 20% of clearance variability was explained by *2 and *3 genotypes, 49% by rifampin, and 8% by body weight. Both, environmental and inherited variability, has to be considered in CYP2C9 metabolized drugs. Clinical Pharmacology & Therapeutics (2005) 77 , P35–P35; doi: 10.1016/j.clpt.2004.12.028