The aim of this study was to characterise the role of the efflux transporter P-glycoprotein in the disposition of cerivastatin. We investigated directional transport characteristics of [14C]cerivastatin across cell monolayers expressing P-glycoprotein (Caco-2 and L-MDR1) and disposition of cerivastatin in mice with disrupted mdr1a and mdr1b genes. The mice were given orally 1 mg/kg cerivastatin and plasma and tissue samples for analysis of cerivastatin were obtained 10, 20, or 30 min after drug administration. Four knock-out mice and four wild-type mice were studied at each time point. In addition, the hypothesis that gemfibrozil-mediated inhibition of P-glycoprotein contributes to the interaction between gemfibrozil and cerivastatin was tested in Caco-2 cells. The apparent permeability coefficient (P(app)) value for the basal-to-apical transport of cerivastatin in Caco-2 and L-MDR1 cell monolayers was 2.4 times (P<0.001) and 3.8 times (P<0.001) as high as the apical-to-basal P(app) value respectively. The P-glycoprotein inhibitor PSC-833 (1 microM) inhibited the net basal-to-apical transport of cerivastatin in Caco-2 monolayers by 35% (P<0.01) and the MRP inhibitor MK-571 (10 microM) by 50% (P<0.01). At concentrations up to 250 microM, gemfibrozil showed no significant effects on the net transport of cerivastatin in Caco-2 cells. The concentration of cerivastatin in the brain at 30 min was 3.1 times higher in the knock-out mice than in the wild-type mice (P<0.05). The brain-to-plasma cerivastatin concentration ratio at 20 min and 30 min was 2.1 (P<0.05) and 3.6 times (P<0.05) higher respectively in the knock-out animals compared with the wild-type animals. Collectively, these results indicate that cerivastatin is a P-glycoprotein substrate, although other transporters probably contribute to cerivastatin transport in humans. As several statins are P-glycoprotein substrates, beneficial as well as adverse effects of the statins might be affected by interindividual differences in P-glycoprotein expression or function caused by, e.g., the MDR1 polymorphism.

A major cause for unpredictable drug response is the enormous variability of drug-metabolizing cytochrome P450s (CYPs) in human liver in which genetic polymorphisms, regulation of gene expression, and physiological factors, including sex, may play a role. To dissect these different factors, we established a large human liver bank with extensive clinical documentation. Recent work concentrated on CYPs 2D6, 2B6, and the 3A family. CYP2D6 expression is highly polymorphic with over 70 alleles. Using liver samples and DNA from phenotyped patients, we further elucidated the genetic basis of phenotypic differences and demonstrated a novel role of alternative splicing, leading to decreased enzyme activity. These studies further emphasize the intricacy of genetic regulation at the CYP2D6 locus. In contrast, CYP2B6, the human orthologue of the rodent phenobarbital-inducible P450 2B, is known to be inducible by a range of substances, but our recent studies also show a high degree of genetic polymorphism. However, the role of polymorphism in determining CYP2B6 expression and function is less decisive as compared with CYP2D6. Thus, with respect to the balance between genetic and nongenetic factors controlling expression, CYP2B6 appears to take an intermediate position. CYP3A4 is the major P450 of human liver and contributes critically to the metabolism of at least half of all drugs. CYP3A4 expression variability is not influenced much by genetic polymorphism. Studies in our liver bank confirm that both induction and down-regulation occur as a consequence of drug treatment. As a further major determinant of hepatic CYP3A4 expression, we found sexual dimorphism, with women expressing at least twice the amount of CYP3A4 protein than men. This surprising result explains the many pharmacokinetic findings of faster metabolism of CYP3A4 drug substrates in women. In conclusion, these data illustrate how various factors contribute to the individual CYP profile in human liver.