Influence of carboxylesterase 2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients
Influence of carboxylesterase 2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients
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DOI：
10.1080/00498250902807338
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发表时间：
2009-01-01
期刊：
影响因子：
1.8
通讯作者：
Suzuki, T.
中科院分区：
文献类型：
--
作者：
Fujiyama, N.;Miura, M.;Suzuki, T.
霉酚酸（MPA）是由前药霉酚酸酯（MMF）转化而来，由肠和肝的酯酶产生。羧酸酯酶（CES）在MMF水解中的作用在体外使用人肝微粒体进行了检查。合并人肝微粒体中MMF水解的Vmax和Km值分别为1368 - 44 nmol min-1 mg-1蛋白和1030 - 65 M。水解活性被CES抑制剂苯甲基磺酰氟、双对硝基苯基磷酸盐和二异丙基氟磷酸盐抑制，IC 50值分别为77.1、3.59和0.0312 M。80名日本肾移植受者接受重复剂量的霉酚酸酯、他克莫司和泼尼松龙，在移植后28天评价MPA药代动力学，以研究MPA药代动力学与CES 2基因多态性之间的关系。CES 2 A4595 G、C8721 T或A-1548 G基因型组之间MPA药代动力学无显著差异。CES 2等位基因变异体似乎也不影响个体之间的血浆MPA浓度。总之，该研究表明，虽然CES 1和/或CES 2参与了MMF水解为MPA，但CES 2等位基因变体似乎对MPA药代动力学的个体间差异仅起很小的作用。
Mycophenolic acid (MPA), converted from the prodrug mycophenolate mofetil (MMF), is generated by intestinal and hepatic esterases. The role of carboxylesterase (CES) in MMF hydrolysis was examined in vitro using human liver microsomes. Vmax and Km values of MMF hydrolysis in pooled human liver microsomes were 1368 44 nmol min-1 mg-1 protein and 1030 65 M, respectively. Hydrolytic activity was inhibited by the CES inhibitors phenylmethylsulfonylfluoride, bis-p-nitorophenylphosphate and diisopropylfluorophosphate, with IC50 values of 77.1, 3.59 and 0.0312 M, respectively. Eighty Japanese renal transplant recipients that received repeated-doses of MMF, tacrolimus and prednisolone, were evaluated for MPA pharmacokinetics 28 days after transplantation to investigate the relationship between MPA pharmacokinetics and CES2 genetic polymorphisms. No significant differences in MPA pharmacokinetics were observed between CES2 A4595G, C8721T or A-1548G genotype groups. CES2 allelic variants also did not appear to affect plasma MPA concentrations between individuals. In conclusion, the study demonstrated that while CES1 and/or CES2 are involved in the hydrolysis of MMF to MPA, CES2 allelic variants appeared to make only a minor contribution to inter-personal differences in MPA pharmacokinetics.