Population pharmacokinetic modelling for enterohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9
Population pharmacokinetic modelling for enterohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9
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DOI：
10.1111/j.1365-2125.2008.03109.x
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发表时间：
2008-06-01
影响因子：
3.4
通讯作者：
Lu, Wei-yue
中科院分区：
文献类型：
--
作者：
Jiao, Zheng;Ding, Jun-jie;Lu, Wei-yue
目的建立基于生理学考虑的麦考酚酸（mycophenolicacid，MPA）肝肠循环（entero-hepatic circulation，EHC）群体药代动力学模型，探讨UGT 1A 9基因多态性对MPA药代动力学的影响。采用非线性混合效应模型建立同时包括MPA及其主要葡糖苷酸代谢产物（MPAG）的EHC模型。以人口统计学特征和UGT 1A 9基因多态性为协变量，选取42名健康男性志愿者，共590个MPA和589个MPAG浓度-时间点。链隔室模型包括肠隔室、胆囊隔室、MPA的中央和外周隔室以及MPAG的中央隔室。MPA和MPAG的典型群体清除率（CL/F）估计值及其相对标准误差分别为10.2 l h（-1）（5.7%）和1.38 l h（-1）（6.9%）。估计体内回收的MPA量占吸收总量的29.1%。协变量分析显示，体重与MPA的CL/F、MPA的室间CL/F和MPA外周室分布容积呈正相关。UGT 1A 9基因多态性对MPA和MPAG的药代动力学无影响。模型评价试验表明，所建模型能较好地描述MPA和MPAG在中国健康受试者体内的药代动力学特征。
AIMSTo establish a population pharmacokinetic model that describes enterohepatic circulation (EHC) of mycophenolic acid (MPA) based on physiological considerations and to investigate the influence of polymorphisms of UGT1A9 on the pharmacokinetics of MPA.METHODSPharmacokinetic data were obtained from two comparative bioavailability studies of oral mycophenolic mofetil formulations. Nonlinear mixed effects modelling was employed to develop an EHC model including both MPA and its main glucuronide metabolite (MPAG) simultaneously. Demographic characteristics and UGT1A9 polymorphisms were screened as covariates.RESULTSIn total, 590 MPA and 589 MPAG concentration-time points from 42 healthy male volunteers were employed in this study. The chain compartment model included an intestinal compartment, a gallbladder compartment, a central and a peripheral compartment for MPA and a central compartment for MPAG. The typical population clearance (CL/F) estimates with its relative standard error for MPA and MPAG were 10.2 l h(-1) (5.7%) and 1.38 l h(-1) (6.9%), respectively. The amount of MPA recycled in the body was estimated to be 29.1% of the total amount absorbed. Covariate analysis showed that body weight was positively correlated with CL/F of MPA, intercompartment CL/F of MPA and distribution volume of MPA peripheral compartment. Polymorphisms of UGT1A9 did not show any effect on the pharmacokinetics of MPA and MPAG. The model evaluation tests indicated that the proposed model can describe the pharmacokinetic profiles of MPA and MPAG in healthy Chinese subjects.CONCLUSIONSThe proposed model may provide a valuable approach for planning future pharmacokinetic-pharmacodynamic studies and for designing proper dosage regimens of MPA.