Fujiyama N, Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Habuchi T, Suzuki T
Department of Pharmacy, Akita University School of Medicine, Akita, Japan.
Xenobiotica. 2009 May;39(5):407-14. doi: 10.1080/00498250902807338.
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. V(max) and K(m) values of MMF hydrolysis in pooled human liver microsomes were 1368 +/- 44 nmol min(-1) mg(-1) protein and 1030 +/- 65 microM, respectively. Hydrolytic activity was inhibited by the CES inhibitors phenylmethylsulfonylfluoride, bis-p-nitorophenylphosphate and diisopropylfluorophosphate, with IC(50) values of 77.1, 3.59 and 0.0312 microM, 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 orA-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.
霉酚酸（MPA）由前体药物霉酚酸酯（MMF）转化而来，由肠道和肝脏酯酶产生。使用人肝微粒体在体外研究了羧酸酯酶（CES）在MMF水解中的作用。在混合的人肝微粒体中，MMF水解的V(max)和K(m)值分别为1368±44 nmol min(-1) mg(-1)蛋白质和1030±65 μM。水解活性受到CES抑制剂苯甲基磺酰氟、双对硝基苯磷酸酯和二异丙基氟磷酸酯的抑制，IC(50)值分别为77.1、3.59和0.0312 μM。对80名接受重复剂量MMF、他克莫司和泼尼松龙的日本肾移植受者在移植后28天进行MPA药代动力学评估，以研究MPA药代动力学与CES2基因多态性之间的关系。在CES2 A4595G、C8721T或A-1548G基因型组之间，未观察到MPA药代动力学有显著差异。CES2等位基因变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CES1和/或CES2参与MMF向MPA的水解，但CES2等位基因变体似乎对MPA药代动力学的个体间差异贡献较小。
