Influence of UGT1A7 and UGT1A9 Intronic I399 Genetic Polymorphisms on Mycophenolic Acid Pharmacokinetics in Japanese Renal Transplant Recipients

Abstract

UGT1A7 and UGT1A9 are uridine diphosphate-glucuronosyltransferase isoforms involved in the glucuronidation of mycophenolic acid (MPA). The aim of this study was to elucidate MPA pharmacokinetics in UGT1A7 and UGT1A9 intronic I399 genotypes in Japanese adult renal transplant recipients. Eighty recipients were given repeated doses of combination immunosuppressive therapy consisting of mycophenolate mofetil and tacrolimus every 12 hours at a designated time (9:00 am and 9:00 pm). On day 28 after renal transplantation, plasma MPA concentrations were measured by high-performance liquid chromatography. All patients had UGT1A9 98TT/-275TT/-2152CC and UGT1A10 177GG/605CC genotypes. The UGT1A7*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 genotypes were detected in 35 (43.8%), five (6.2%), 28 (35.0%), eight (10.0%), and four (5.0%) patients, respectively, and the UGT1A9 I399C/C, C/T, and T/T genotypes were detected in 12 (15.0%), 33 (41.2%), and 35 (43.8%) patients of the 80 Japanese recipients. There were no significant differences in MPA pharmacokinetics among UGT1A7 or UGT1A9 intronic I399 genotype groups. The mean dose-adjusted area under the plasma concentration-time curve from zero to 12 hours (AUC0-12) of MPA in UGT1A7*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 were 95, 98, 99, 88, and 86 ng.h/mL/mg, respectively (P = 0.9475). The mean dose-adjusted AUC0-12 of MPA in UGT1A9 I399C/C, C/T, and T/T were 87, 99, and 95 ng.h/mL/mg, respectively (P = 0.6937). The dose-adjusted trough levels of MPA in UGT1A9 I399C/C, C/T, and T/T were 5.4, 5.5, and 4.7 ng/mL/mg (P = 0.5845). Although UGT1A7*3 and UGT1A9 I399C/C are known to have low-activity variants when studied in vitro, they do not have reduced in vivo MPA glucuronidation activity. UGT1A7 and UGT1A9 I399 polymorphisms do not contribute to interindividual differences in MPA pharmacokinetics.