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

作　　者：Xiao-chun XIE Jun LI Hong-yang WANG Hong-liang LI Jing LIU Qian FU Jia-wen HUANG Chen ZHU Guo-ping ZHONG Xue-ding WANG Ping-ping SUN Min HUANG Chang-xi WANG Jia-li LI 

机构地区：[1]Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China [2]Kidney Transplant Department, Transplant Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China [3]Department of Pharmacy, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China

出　　处：《Acta Pharmacologica Sinica》2015年第5期644-650,共7页中国药理学报（英文版）

摘　　要：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 UGTIA9 -1818T〉C, 1399C〉T, -118T9/10, -440C〉T, -331T〉C, UGT2B7 IVS1＋985A〉G, 211G〉T, -900A〉G, UGT1A8 518C〉G and UGTIA7 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 AUCo_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 AUCo_12 h of the patients with the UGTIA 7 622CC and UGTIA9 -440CT/-331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and -440C/-331T homozygotes. Furthermore, the genotypes UGTIA9 -1818T〉C and UGTIA8 518C〉G were associated with a low dose-adjusted MPAG AUCo_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.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 UGTIA9 -1818T〉C, 1399C〉T, -118T9/10, -440C〉T, -331T〉C, UGT2B7 IVS1＋985A〉G, 211G〉T, -900A〉G, UGT1A8 518C〉G and UGTIA7 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 AUCo_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 AUCo_12 h of the patients with the UGTIA 7 622CC and UGTIA9 -440CT/-331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and -440C/-331T homozygotes. Furthermore, the genotypes UGTIA9 -1818T〉C and UGTIA8 518C〉G were associated with a low dose-adjusted MPAG AUCo_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.

关 键 词：renal transplantation IMMUNOSUPPRESSANT mycophenolate mofetil mycophenolic acid 7-O-MPA-glucuronide PHARMACOKINETICS UDP-GLUCURONOSYLTRANSFERASES genetic polymorphisms 

分 类 号：Q538[生物学—生物化学] Q954.5