The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients

Abstract

Background: Mycophenolic acid (MPA), an effective immunosuppressive drug used in renal transplantation, is extensively glucuronidated by several uridine diphosphate-glucuronosyltransferases (UGTs) into an inactive 7-O-glucuronide and, to a lesser extent, into a pharmacologically active acyl-glucuronide. Experiments using human liver microsomes have shown that T--275A and C--2152T single-nucleotide polymorphisms (SNPs) of the UGT1A9 promoter region are associated with higher hepatic expression of UGT1A9 and increased in vitro glucuronidation activity for MPA.

Methods: The distribution of UGT1A9 promoter region T-275A and C-2152T SNPs and the less frequent UGT1A9*3 coding region mutation, which results in decreased in vitro activity, was determined in 95 de novo renal recipients. The impact of these UGT1A9 SNPs on early clinical MPA pharmacokinetics was evaluated.

Results: Only in patients taking 2 g mycophenolate mofetil daily was a decreased MPA exposure observed in those who carried either the T-275 A or the C-2152 T polymorphism (or both) compared with those who did not (area under concentration-time curve [AUC] from 0 to 12 hours, 31.7+/--17.6 mg.h/L versus 63.6+/--30.9 mg.h/L [P=.009]; predose trough plasma concentration, 1.23 +/--.25 mg/L versus 2.84+/--1.64 mg/L [P=.04]). The partial MPA AUC from 6 to 12 hours (AUC6--12)-an estimate of MPA enterohepatic recirculation-and the ratio between partial MPA AUC6--12 and dose-interval AUC from 0 to 12 hours decreased when either or both UGT1A9 promoter region SNPs were present (AUC6--12, 6.2+/-5.4 mg.h/L versus 21.5+/-14.9 mg.h/L [P=.002]; ratio, 18.4%+/- 7.8% versus 31.7%+/- 8.8% [P=.002]).

Conclusion: The T-275A and C-2152T SNPs of the UGT1A9 gene promoter are associated with significantly lower MPA exposure in renal recipients treated with 2 g mycophenolate mofetil daily, and part of this effect is caused by interruption of enterohepatic recirculation of MPA.