Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients

作者：Xie, Xiao-chun; Li, Jun; Wang, Hong-yang; Li, Hong-liang; Liu, Jing; Fu, Qian; Huang, Jia-wen; Zhu, Chen; Zhong, Guo-ping; Wang, Xue-ding; Sun, Ping-ping; Huang, Min; Wang, Chang-xi; Li, Jia-li

来源：Acta Pharmacologica Sinica, 2015, 36(5): 644-650.

DOI：10.1038/aps.2015.7

• renal transplantation
• immunosuppressant
• mycophenolate mofetil
• mycophenolic acid
• 7-O-MPA-glucuronide
• pharmacokinetics
• UDP-glucuronosyltransferases
• genetic polymorphisms

Aim: To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients. @@@ Methods: A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 -1818T>C, I399C>T, -118T9/10, -440C>T, -331T>C, UGT2B7 IVS1+985A>G, 211G>T, -900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics. @@@ Results: The dose-adjusted MPA AUC(0-12) (h) of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC0-12 h of the patients with the UGT1A7 622CC and UGT1A9 -440CT/-331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and -440C/-331T homozygotes. Furthermore, the genotypes UGT1A9 -1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC(0-12) (h). @@@ Conclusion: The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.

• 出版日期2015-5
• 单位中山大学