基于生理药动学模型预测乌头碱在人体的药动学行为

Predicting pharmacokinetic behavior of aconitine in humans based on physiological pharmacokinetic model

目的 建立乌头碱大鼠生理药动学模型,并外推至中国健康成年男性,预测乌头碱在人体内的药动学行为。方法查阅文献获取乌头碱理化、生化参数以及药动学数据,采用GastroPlus软件构建并验证大鼠生理药动学模型,比较预测与观测的药时曲线及主要药动学参数,并进一步外推至中国健康成年男性。结果 构建的大鼠生理药动学模型其主要药动学参数达峰浓度(C_(max))、达峰时间(T_(max))、药时曲线下面积(AUC_(0-t))、AUC_(0-inf)预测值与观测值之比均在0.5~2倍误差范围内,且预测值与实验值的平均折叠误差以及绝对平均折叠误差均可接受范围内,并利用已构建成功的大鼠生理药动学模型外推至中国健康成年男性预测其药动学行为。结论 成功构建大鼠生理药动学模型,并且在此基础上外推至人,预测人体药动学行为,为临床上高效安全使用乌头碱提供依据,同时为含乌头碱类中药的风险评估提供思路。

Objective To establish a physiological pharmacokinetic model of aconitine in rats and extrapolate it to healthy Chinese adult males to predict the pharmacokinetic behavior of aconitine in humans. Methods The literature was reviewed to obtain physicochemical and biochemical parameters as well as pharmacokinetic data of aconitine, and GastroPlus software was used to construct and validate a physiologically based pharmacokinetic model in rats. The predicted and observation pharmacokinetic curves and major pharmacokinetic parameters were compared. And further extrapolate to healthy Chinese adult males. Results The main pharmacokinetic parameters of the constructed rat physiological pharmacokinetic model, C_(max), T_(max), AUC_(0-t)and AUC_(0-inf) were within 0.5—2 times the error range of the predicted and observation values, and the mean collapse error and absolute mean collapse error of the predicted and experimental values were within acceptable limits. The pharmacokinetic behaviors were extrapolated to healthy Chinese adult males. Conclusion The physiological pharmacokinetic model of rats was successfully constructed and extrapolated to humans to predict the pharmacokinetic behavior in humans, which provides a basis for the efficient and safe use of aconitine in clinical practice, as well as an idea for the risk assessment of aconitine-containing Chinese medicines.