Quantitative Population Pharmacokinetic Analysis of Pravastatin Using an Enterohepatic Circulation Model Combined With Pharmacogenomic Information on SLCO1B1 and ABCC2 Polymorphisms
Quantitative Population Pharmacokinetic Analysis of Pravastatin Using an Enterohepatic Circulation Model Combined With Pharmacogenomic Information on SLCO1B1 and ABCC2 Polymorphisms
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DOI：
10.1177/0091270009341960
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发表时间：
2009-11-01
影响因子：
2.9
通讯作者：
Ieiri, Ichiro
中科院分区：
文献类型：
--
作者：
Ide, Takafumi;Sasaki, Tomohiro;Ieiri, Ichiro
本研究的目的是建立普伐他汀在肝肠循环（EHC）中的群体药代动力学（PPK）模型，并定量评价SLCO 1B 1和ABCC 2基因多态性对普伐他汀药代动力学（PK）特征的影响。共使用了来自57名健康男性志愿者的636份血液样本。使用非线性混合效应模型（NONMEM）进行PPK分析，并通过自助分析进行验证。普伐他汀的PK特征最好用Erlang分布的EHC模型描述。协变量分析显示，SLCO 1B 1 *15显著影响相对生物利用度（F-rel）;与无 *15等位基因的受试者相比，杂合子和纯合子受试者的F-rel分别增加了1.50倍和1.95倍。未发现ABCC 2多态性是普伐他汀的潜在协变量。Bootstrap分析表明，所提出的PPK模型可充分描述普伐他汀的PK特征。SLCO 1B 1 *15对F-rel具有显著影响，表明OATP 1B 1是普伐他汀全身暴露的决定因素之一。
The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 636 blood samples from 57 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1*15 significantly influenced relative bioavailability (F-rel); F-rel was increased 1.50- and 1.95-fold in participants heterozygous and homozygous, respectively, for the *15 allele in comparison with participants without the allele. No ABCC2 polymorphism was identified as a potential covariate for pravastatin. The bootstrap analysis indicated that the PK profile of pravastatin was adequately described by the proposed PPK model. SLCO1B1*15 has a significant effect on F-rel, indicating that OATP1B1 is one of the determinants of systemic exposure to pravastatin.