Estimation of Interindividual Variability of Pharmacokinetics of CYP2C9 Substrates in Humans.

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 (CLint,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 (CLoral) values in a Monte Carlo simulation with a dispersion model. The CVs for tolbutamide CLint,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 CLoral 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 CLint,h,CYP2C9 variability together with the variabilities of other isoforms are useful for predicting the AUC variability of CYP2C9 substrates.

Prediction of inter-individual variability in the pharmacokinetics of CYP2C19 substrates in humans.

Significant inter-individual variability of exposure for CYP2C19 substrates may be only partly due to genetic polymorphism. Therefore, the in vivo inter-individual variability in hepatic intrinsic clearance (CL(int,h)) of CYP2C19 substrates was estimated from reported AUC values using Monte Carlo simulations. The coefficient of variation (CV) for CL(int,h) in poor metabolizers (PM) expected from genotypes CYP2C19*2/*2, CYP2C19*3/*3 or CYP2C19*2/*3 was estimated as 25.8% from the CV for AUC of omeprazole in PMs. With this, CVs of CL(int,h) in extensive metabolizers (EM: CYP2C19*1/*1), intermediate metabolizers (IM: CYP2C19*1/*2 or *3) and ultra-rapid metabolizers (UM), CYP2C19*17/*17 and *1/*17, were estimated as 66.0%, 55.8%, 6.8% and 48.0%, respectively. To validate these CVs, variability in the AUC of CYP2C19 substrates lansoprazole and rabeprazole, partially metabolized by CYP3A4 in EMs and IMs, were simulated using the CV in CL(int,h) for CYP2C19 EMs and IMs and 33% of the CV previously reported for CYP3A4. Published values were within 2.5-97.5 percentile range of simulated CVs for the AUC. Furthermore, simulated CVs for the AUC of omeprazole and lansoprazole in ungenotyped populations were comparable with published values. Thus, estimated CL(int,h) variability can predict variability in the AUC of drugs metabolized not only by CYP2C19 but also by multiple enzymes.