Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients

Abstract

UGT1A8 and UGT2B7 are important uridine diphosphate-glucuronosyltransferase isoforms for the glucuronidation of mycophenolic acid (MPA). The aim of this investigation was to elucidate MPA pharmacokinetics in UGT1A8 and UGT2B7 genotypes in Japanese renal transplant recipients. Seventy-two recipients received repeated doses of mycophenolate mofetil and tacrolimus. On day 28 after renal transplantation, plasma MPA concentrations were measured for the next 24 h using high-performance liquid chromatography. UGT1A8*2 (A(173)G) and UGT2B7*2 (Y(268)) were detected using a PCR-RFLP-based procedure. There were no significant differences in daytime and nighttime pharmacokinetics of MPA between UGT1A8 or UGT2B7 genotypes. The mean daytime dose-adjusted AUC(0-12) of MPA in UGT1A8*1/*1, *1/*2 and *2/*2 were 2.47, 2.33 and 2.57 ng.h/ml/mg/kg (P = 0.7711), and the mean nighttime AUC(0-12) were 2.15, 2.00 and 2.08 ng.h/ml/mg/kg (P = 0.4656). The mean daytime and nighttime dose-adjusted AUC(0-12) of MPA in UGT2B7*1/*1, *1/*2 and *2/*2 were 2.61, 2.24 and 2.03 ng.h/ml/mg/kg and 2.18, 1.94, and 1.45 ng.h/ml/mg/kg, respectively (P = 0.3475 and 0.2575). The mean nighttime C(max), t(max), and AUC(6-12)/AUC(0-12) ratio (enterohepatic circulation and recirculation ratio) of MPA in all UGT1A8 and UGT2B7 genotypes were lower, longer, and higher, respectively, than the daytime values. Both UGT1A8 and UGT2B7 allelic variants seem not to affect Japanese interindividual variability for plasma MPA concentration. Regardless of UGT1A8 and UGT2B7 genetic polymorphisms, the absorption of MPA through enterohepatic recirculation is higher at night.