Drug-Drug Interaction Between Oxycodone and Diazepam by a Combined in Silico Pharmacokinetic and Pharmacodynamic Modeling Approach.
Drug-Drug Interaction Between Oxycodone and Diazepam by a Combined in Silico Pharmacokinetic and Pharmacodynamic Modeling Approach.
复制标题
DOI：
10.1021/acschemneuro.0c00810
复制
发表时间：
2021-05-19
影响因子：
5
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Ji B;Xue Y;Xu Y;Liu S;Gough AH;Xie XQ;Wang J
阿片类药物和苯二氮卓类药物具有复杂的药物-药物相互作用（ddi），是药物不良反应的重要来源。本研究采用计算机药代动力学（PK）和药效学（PD）建模和模拟的方法，预测氧可酮（OXY）和地西泮（DZP）在人体内的DDI。首先，我们采用基于生理的药代动力学（PBPK）模型研究了OXY和DZP之间的PK相互作用。其次，应用分子对接、分子动力学（MD）模拟、分子力学/泊松-玻尔兹曼表面积（MM-PBSA）自由能等分子模型技术预测两种药物之间的PD-DDI。PBPK模型预测的OXY与DZP的PK互作作用不明显。在正常剂量下，两种药物之间没有观察到显著的相互作用，尽管非常高剂量的DZP对氧代谢表现出不可忽视的抑制作用。另一方面，分子模型研究表明，DZP在活性μ -阿片受体（MOR）和κ-阿片受体（KOR）的同一结合口袋上具有与OXY竞争的潜力。MD模拟和MM-PBSA计算结果表明，OXY和DZP结合阿片受体之间可能存在协同作用，OXY可能靶向活性的MOR，而DZP选择性地结合活性的KOR。因此，药代动力学对OXY和DZP之间的DDI有轻微影响，尽管DZP过量已引起注意。在揭示OXY与DZP之间DDI作用机制方面，药效学可能比药代动力学发挥更重要的作用。
Opioids and benzodiazepines have complex drug-drug interactions (DDIs), which serve as an important source of adverse drug effects. In this work, we predicted the DDI between oxycodone (OXY) and diazepam (DZP) in the human body by applying in silico pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation. First, we studied the PK interaction between OXY and DZP with a Physiologically-based Pharmacokinetic (PBPK) model. Second, we applied molecular modeling techniques including molecular docking, molecular dynamics (MD) simulation, and the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) free energy method to predict the PD-DDI between these two drugs. The PK interaction between OXY and DZP predicted by the PBPK model was not obvious. No significant interaction was observed between the two drugs at normal doses, though very high doses of DZP demonstrated a non-negligible inhibitory effect on OXY metabolism. On the other hand, molecular modeling study shows DZP has the potential to compete with OXY at the same binding pocket of the active µ-opioid receptor (MOR) and κ-opioid receptor (KOR). MD simulation and MM-PBSA calculation results demonstrated that there is likely a synergetic effect between OXY and DZP binding to opioid receptors, as OXY is likely to target the active MOR while DZP selectively binds to the active KOR. Thus, pharmacokinetics contributes slightly to the DDI between OXY and DZP although an overdose of DZP has been brought to attention. Pharmacodynamics is likely to play a more important role than pharmacokinetics in revealing the mechanism of DDI between OXY and DZP.
登录
查看更多内容
影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
3.4
作者：
DIVOLL, M;GREENBLATT, DJ;SHADER, RI
通讯作者：
SHADER, RI
影响因子：
120.7
作者：
GREENBLATT, DJ;WOO, E;SHADER, RI
通讯作者：
SHADER, RI
影响因子：
4.1
作者：
He, Xibing;Liu, Shuhan;Wang, Junmei
通讯作者：
Wang, Junmei
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML