丹酚酸A对大鼠血浆中同型半胱氨酸调节作用的药动学-药效学结合模型

任欣怡; 陈渊成; 王琰; 肖媛媛; 柳晓泉

丹酚酸A对大鼠血浆中同型半胱氨酸调节作用的药动学-药效学结合模型

Pharmacokinetic-pharmacodynamic(PK-PD) modeling of salvianolic acid A on the plasma homocysteine in rats

摘要

摘要: 同型半胱氨酸(Hcy)是独立的心血管危险因子，降低Hcy水平有利于减少心血管疾病风险。以大鼠急性蛋氨酸(Met)负荷作为药理模型，就丹参水溶性物质主要活性成分丹酚酸A(SalA)对大鼠血浆中Hcy调节作用进行了药动学和药效学研究，发现1，2.5，5 mg/kg 3个剂量的SalA对Met负荷引起的血浆中总同型半胱氨酸（tHcy）升高有降低作用，并且存在一定的剂量依赖性。本文建立了基于SalA对Hcy调节作用机制的药动学-药效学结合(PK-PD)模型，较好的拟合了药动学和药效学的实验结果，并与丹参素(DSS)对Hcy调节作用的PK-PD模型结果进行比较，定量揭示了SalA对tHcy升高促进作用以及转硫途径消除作用与DSS的差异：SalA对于tHcy上升促进作用弱于DSS，但是对于tHcy转硫途径消除的作用强于DSS。

Abstract: Elevated plasma total homocysteine (tHcy) level has been acknowledged as an independent risk factor for cardiovascular diseases.Salvianolic acid A (SalA) is one of the major active water-soluble ingredients of Salvia miltiorrhiza.The pharmacokinetics (PK) and pharmacodynamics (PD) of SalA on plasma tHcy in methionine-loading rats was evaluated.Acute treatment with a single dose of SalA (1,2.5,5 mg/kg) in rats with Met loading significantly reduced the plasma tHcy level in a dose-dependent manner.In order to characterize the effect of SalA on plasma tHcy，a mechanism-based PK-PD model was developed.Modeling and simulations well fitted the measured values.By comparison with the PK-PD model of danshensu(DSS)，it was found that the elevated effect of SalA on tHcy by methylation was weaker than that of DSS,while trans-sulfuration promotion effect of SalA on tHcy was greater than that of DSS.

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