Impact of the CYP3A5 polymorphism on the metabolic disposition of calcineurin inhibitors

Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, are the mainstay for immunosuppression therapy after liver transplantation. However, even with therapeutic monitoring, they are still associated with many dose-limiting toxicities, especially nephrotoxicity. It has been suggested that the systemic and renal disposition, and the metabolite profiles of CNIs play important roles in defining the risk of CNI-induced renal toxicity. CNIs are substrates for CYP3As and P-glycoprotein. Both genetic and environmental factors that influence the activity of these proteins are thought to contribute to the high degree of inter-individual variability of CNI clearance. The purpose of this thesis investigation was to identify the impact of the newly discovered CYP3A5 genetic polymorphism on the metabolism of CNIs.; The contribution of CYP3A4 and CYP3A5 to the intrinsic clearance and the metabolite profiles of cyclosporine and tacrolimus in liver and kidney were evaluated using heterologously expressed CYP3A enzymes, and CYP3A5-genotyped human liver and kidney microsomes. For cyclosporine, the intrinsic clearance of total metabolite formation was higher for CYP3A4 compared with CYP3A5. However, the formation of primary and secondary metabolites were higher in microsomes from CYP3A5*1/*3 donors compared with those from CYP3A5*3/*3 donors. These secondary metabolites have been associated with increased risk of nephrotoxicity. These results indicated that inheritance of the CYP3A5*1 allele may influence (e.g. increase) the risk of cyclosporine-induced renal toxicity.; In contrast to cyclosporine, the intrinsic clearance of total metabolite formation was higher for CYP3A5 compared with CYP3A4. The formation of 13-DMT, 12-HT and 31-DMT were higher in microsomes with a CYP3A5*1/*3 genotype compared with a CYP3A5*3/*3 genotype. The results suggest that inheritance of the CYP3A5*1 allele, and associated intra-renal tacrolimus metabolism may reduced the risk of tacrolimus-induced nephrotoxicity.; Other factors that might influence tacrolimus disposition during an early stage (0--35 days) after liver transplantation were evaluated using a prospective study and population pharmacokinetic analysis. The analysis revealed that liver function (AST and prothrombin time) and hernatocrit were covariates for apparent tacrolimus clearance. Recipient (e.g. intestinal and renal) CYP3A5 and MDR1 genotypes were not covariates for tacrolimus clearance. These results could be used in combination with the donor liver CYP3A5 genotype to optimize tacrolimus dose adjustments in liver transplant patients.; In summary, CYP3A5 polymorphism had a significant impact on the metabolic clearance of tacrolimus and cyclosporine, and may influence the risk of CNI-induced nephrotoxicity.