[关键词]
[摘要]
目的 基于生理驱动建立生理药动学(PBPK)模型,以酒石酸美托洛尔缓释片、氨茶碱缓释片、吲达帕胺缓释片和奥美拉唑肠溶片为工具药进行模型预测准确性考察。方法 将氨茶碱缓释片、酒石酸美托洛尔缓释片、奥美拉唑肠溶片、吲达帕胺缓释片的相关参数带入生理驱动V1.0平台,预测血药浓度,计算药动学参数。雄性Beagle犬ig受试药物1片(吲哒帕胺缓释片1.5 mg、奥美拉唑肠溶片60 mg、酒石酸美托洛尔缓释片50 mg、氨茶碱缓释片100 mg),于给药前和给药后0.5、1.0、1.5、2.0、3.0、4.0、5.0、7.0、9.0、12.0、16.0、24.0、36.0、48.0 h犬前肢静脉取血;建立超高效液相色谱-三重四级杆串联质谱(UPLC-MS/MS)法检测Beagle犬血药浓度,并计算药动学参数。对血药浓度预测结果和实测结果进行相关性分析;对药动学参数进行误差分析。结果 成功建立基于生驱动的人体及比格犬外推PBPK模型,氨茶碱缓释片、酒石酸美托洛尔缓释片、奥美拉唑肠溶片血药浓度实测值与预测值较接近,吲达帕胺缓释片的实测峰浓度低于预测值,相关系数分别为0.933 1、0.974 3、0.918 8、0.965 8。药动学参数误差分析Cmax误差分别为22%、27%、10%、32%,AUC误差分别为-13%、-9%、-14%、-6%,Tmax的误差分别为-40%、-15%、25%、-110%,t1/2的误差分别为-17%、-11%、-46%、52%。Tmax和t1/2的预测与实测值差距较大,对奥美拉唑肠溶片的预测误差均小于25%,预测准确。吲达帕胺缓释片的Cmax和t1/2预测误差均较大,可能是犬的消化道内的消化液的总量比人少,使难溶性药物吲达帕胺的溶解更加困难造成的。结论 基于生理驱动的PBPK模型能比较准确的预测生物药剂学分类系统(BCS)Ⅰ类的酒石酸美托洛尔缓释片、氨茶碱缓释片、Ⅱ类吲达帕胺缓释片和奥美拉唑肠溶片的吸收程度与药动学特征。
[Key word]
[Abstract]
Objective Based on the physiological engine PBPK model, the prediction accuracy was evaluated with metoprolol sustained-release tablets, aminophylline sustained-release tablets, indapamide sustained-release tablets and omeprazole entericcoated tablets as tool drugs. Methods The related parameters of aminophylline sustained-release tablets, metoprolol tartrate sustained-release tablets, omeprazole enteric coated tablets and indapamide sustained-release tablets were brought into the physiological driving v1.0 platform to predict the blood concentration and calculate the pharmacokinetic parameters. One tablet (indapamide 1.5 mg, omeprazole 60 mg, metoprolol tartrate 50 mg, aminophylline 100 mg) was given to male beagle dogs. Venous blood collected from dog forelimb before administration and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 7.0, 9.0, 12.0, 16.0, 24.0, 36.0, 48.0 h after administration. A method of ultra-high performance liquid chromatography triple quadrupole tandem mass spectrometry (UPLC-MS/MS) was established for the determination of beagle dogs' blood drug concentration, and the pharmacokinetic parameters were calculated. The correlation between the predicted results and the measured results was analyzed, and the error of pharmacokinetic parameters was analyzed. Results Successfully established a human-driven human body and beagle dog extrapolation PBPK model, The predicted results of the aminophylline sustained-release tablets, omeprazole enteric-coated tablets, metoprolol sustained-release tablets and indapamide sustained-release tablets in the Beagle dog extrapolation model compared with Beagle's in vivo data, The correlation is 0.9331, 0.9743, 0.9188, 0.9658, The Cmax error of the pharmacokinetic parameter error analysis were 22%, 27%, 10%, 32%, AUC errors were-13%,-9%,-14%,-6%, The error of Tmax were-40%,-15%, 25%,-110%, The error of T1/2 were-17%,-11%,-46%, 52%. The difference between Tmax and t1/2 were large, and the prediction error of omeprazole enteric coated tablets was less than 25%. The Cmax and t1/2 prediction errors of indapamide sustained-release tablets are large, which may be caused by the fact that the total amount of digestive fluid in the digestive tract of dogs is less than that of people, making the dissolution of indapamide more difficult. Conclusion The PBPK model based on physiological engine could accurate predict pharmacokinetic characteristics.of the absorption with metoprolol sustained-release tablets, aminophylline sustained-release tablets (BCSI), class indapamide sustained-release tablets and omeprazole enteric-coated tablets(BCSII).
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[基金项目]
广东省基础与应用基础研究基金项目(2020A1515010156);广东省普通高校人工智能重点领域专项(2019KZDZX1006);2019年度广东省重点学科科研项目