We demonstrated that ABCB1 polymorphisms may influence the AED responsiveness without significant changes in the plasma concentrations of CBZ. Our findings were the inverse of previous results in European epileptics, thus the influence of ABCB1 polymorphisms on the AED responsiveness and/or the P-glycoprotein activity may vary among races.

The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.

A nonlinear mixed-effect modeling (NONMEM) program was used to evaluate the effects of cytochrome P450 (CYP) 2C9 and CYP2C19 polymorphisms on the phenobarbital (PB) population clearance for Japanese epileptics. The pharmacokinetics of the 260 PB concentrations at a steady-state obtained from 79 patients was described with a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight (BW), age, gender, PB daily dose, CYP2C9 and CYP2C19 genotypes, the coadministered antiepileptic drugs (AEDs), and complications. The final model of PB apparent clearance was as follows: CL = 0.23 x (BW/40)0.21 x 0.52CYP2C9*1/*3 x 0.68VPA x 0.85PHT x 0.85SMID x (1 + etaCL) where CL = the clearance of PB; CYP2C9*1/*3 = 1, otherwise 0; VPA = 1 if valproic acid is coadministered, otherwise 0; PHT = 1 if phenytoin is coadministered, otherwise 0; SMID = 1 if complications of severe or profound mental retardation with a significant behavior impairment are presented, otherwise 0; and etaCL = the independent random error distributed normally with the mean zero and variance equal to omegaP2. The total clearance of PB decreased by 48% in patients with CYP2C9*1/*3 genotype in comparison with those with CYP2C9*1/*1 genotype (P < 0.001). An effect of CYP2C19 polymorphisms was not detected. To our knowledge, this is the first report to demonstrate that the CYP2C9 genotype affects the PB metabolism in routine care, but the results should be further verified in other ethnic populations.

Our data obtained from subjects whose CYP3A activities were also induced by carbamazepine itself coincided with their results. In these studies of Asian subjects the induced CYP3A activities in the CYP3A*3/*3 subjects lacking CYP3A5 were not inferior to those in the rest. Large racial differences in the frequencies of the CYP3A5 variants and haplotypes have been reported. 1,4 The mechanism(s) regulating the hepatic CYP3A expression may also be different among races because the level of CYP3A4 messenger ribonucleic acid did not correlate with the level of CYP3A5 messenger ribonucleic acid in livers in Japanese subjects in contrast to the coregulatory expression of CYP3A4 and CYP3A5 in livers in white subjects. 4,5 Mouly et al 2 questioned whether the effect of CYP3A5 genotype observed in healthy volunteers might be evident in treated patients with human immunodeficiency virus, and this remains unanswered. The clinical impact of the CYP3A5*3 genotypes should thus be clarified further with regard to the influences of substrates, multigene haplotypes, races, and environmental factors. 1,2