Estimation of Interindividual Variability of Pharmacokinetics of CYP2C9 Substrates in Humans

Abstract

The activity of metabolic enzymes varies across individuals and populations. Activity varies even among individuals sharing the same genotype. Genetic polymorphisms in CYP2C9 cause significant interindividual variability in the metabolism of its substrates. However, the variability of CYP2C9 intrinsic hepatic clearance (CL_int,h,CYP2C9) among subjects of the same genotype has not been reported. In this study, we estimated the coefficient of variation (CV) for the intrinsic hepatic clearance of tolbutamide by CYP2C9 for each CYP2C9 genotype using previously reported area under the blood concentration curve (AUC) and oral clearance (CL_oral) values in a Monte Carlo simulation with a dispersion model. The CVs for tolbutamide CL_int,h,CYP2C9 were estimated to be 18.1%, 23.9%, 25.4%, 22.3%, 13.0%, and 19.8% for CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. These values are smaller than those previously reported for CYP2D6*1/*1 (43%), CYP2C19*1/*1 (66%), and CYP3A4 (33%). These CV values were used to predict AUC and CL_oral variability of other CYP2C9 substrates, which are also substrates of other CYP isoforms. Then, the estimated CVs were consistent with those reported in previous studies of genotyped and ungenotyped subjects. Our estimates of CL_int,h,CYP2C9 variability together with the variabilities of other isoforms are useful for predicting the AUC variability of CYP2C9 substrates.

Keywords: CYP enzymes; Monte Carlo simulation; in silico modeling; pharmacogenetics; pharmacokinetics.