普伐他汀在健康受试者中的生理药动学研究

Physiologically based pharmacokinetics of pravastatin in healthy volunteers

目的:考察口服普伐他汀在健康受试者体内的生理药动学(PBPK)模型。方法:收集文献报道的理化性质和体外酶促动力学数据,结合人口统计学资料,建立普伐他汀在人体的生理药动学模型。预测单剂量口服10,20,40 mg普伐他汀的血药浓度-时间曲线,并用文献药时曲线和药动学参数实测值验证已建立的模型,预测各剂量在不同组织内的分布情况。结果:本文建立的生理药动学模型中,药时曲线预测值与实测值相符合,预测的不同剂量药动学参数(AUC,Cmax,Tmax)与实测值基本一致(倍数误差<1.5),模型准确可靠。模型预测结果显示,普伐他汀分布在各组织中,其中肺和心脏分布较多,Cmax分别为(8.14,33.23,71.64ng·m L-1),(7.47,29.91,64.93 ng·m L-1);脑和肌肉分布较少,Cmax分别为(5.60,21.39,46.99 ng·m L-1),(5.03,18.93,43.46 ng·m L-1)。结论:普伐他汀主要分布在肺和心脏,脑和肌肉分布较少,3个剂量组的组织分布趋势相同,含量呈剂量依赖性上升。

Objective： To investigate the physiologically based pharmacokinetic（ PBPK） model of oral pravastatin in healthy volunteers. Methods： Based on the physicochemical properties,the enzyme kinetic parameters published in literature and demographic data,a physiologically based pharmacokinetic model of pravastatin for human was built. The plasma concentration-time profiles after single dose administration of pravastatin 10,20 or40 mg in healthy subjects were predicted. Model validation was conducted after a comparison of the simulated concentrations in plasma and pharmacokinetic parameters with the observed data in literature. Finally,the PBPK model was employed to predict the distribution of oral pravastatin at various doses in various tissues of human. Results：The simulated plasma profiles matched well with the observed profiles for all of doses ranging from 10 mg to 40 mg using the PBPK model. The predicted pharmcokinetic parameters（ AUC,Cmaxand Tmax） were reasonably consistent（ 〈 1. 5-fold error） with the observed values after single oral administration of pravastatin in the reported healthy adult population groups. The PBPK model was stable and reliable. Pravastatin was extensively distributed in most tissues,especially in the lung and heart,where Cmaxwere（ 8. 14,33. 23 and 71. 64 ng·m L-1） and（ 7. 47,9. 91 and 64. 93 ng·m L-1） after dosing of 10,20 and 40 mg,respectively. Less pravastatin was concentrated in the brain and muscle,where Cmaxwere（ 5. 60,21. 39 and 46. 99 ng·m L-1） and（ 5. 03,18. 93 and 43. 46 ng·m L-1）. Conclusion： The PBPK model shows that pravastatin is mainly distributed in lung and heart,but less in brain and muscle. The distribution behavior is similar in three dose groups. Pravastatin concentration in tissues increases in a dose-dependent manner.