The assessment of drug interactions for a simple turnover system when the basic pharmacodynamic response is governed by indirect mechanisms was explored. This report describes a diverse array of possible in vivo pharmacodynamic effects from a combination of two drugs acting by similar or different indirect mechanisms. Various conditions of pharmacodynamic drug combinations were explored mathematically and by simulation: (a) interactions of two drugs acting simultaneously either on the production (k(in)) or on the dissipation (k(out)) processes controlling the in vivo response by competitive (four cases) or non-competitive interaction (six cases); and (b) combinations of two drugs acting on separate k(in) and k(out) processes simultaneously (four cases). A range of different combinations of drug doses was used. Plasma concentration time profiles were generated according to monoexponential disposition. Pharmacodynamic response profiles were simulated using the above conditions and characterized by descriptors such as Area Between Effect (and Baseline) Curve (ABEC) values. The interaction of agents by competitive mechanisms produced net responses that were additive in nature. Response profiles for non-competitive interactions on the same process were both antagonistic (for two drugs with effects that oppose each other) and synergistic (for two drugs that produce the same response). On the other hand, response signatures for agents acting non-competitively on the production and dissipation factors by opposing mechanisms (e.g. inhibiting k(in) plus stimulating k(out)) showed dramatic changes in net effects and produced apparent drug synergy. Net indirect response profiles for joint use of two or more drugs measured by ABEC values may look "additive", "antagonistic", or "synergistic" depending on doses, their intrinsic potencies, the nature of interaction (competitive or non-competitive) as well as their mechanisms of action. These models may help explain changes in pharmacologic responses to two agents in a more rational and mechanistic fashion than older empirical methods.

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评估与药效间接反应模型相关的药物相互作用。

探索了一种简单的周转系统，当基本药效学反应受间接机制控制时，药物相互作用的评估。该报告描述了两种药物通过相似或不同的间接机制共同作用所产生的多种体内药效学作用。通过数学和模拟研究了多种药效学药物组合的条件：（a）两种药物的相互作用同时作用于生产（k（in））或耗散（k（out））过程，通过竞争控制体内反应（四宗）或非竞争性互动（六宗）；（b）同时作用于独立的k（in）和k（out）过程的两种药物的组合（四种情况）。使用了一系列不同剂量的药物。根据单指数布置产生血浆浓度时间曲线。使用上述条件模拟了药效学响应曲线，并用诸如效应（和基线）曲线之间的面积（ABEC）值之类的描述符进行了表征。药物通过竞争机制的相互作用产生了本质上可加的净反应。在同一过程中非竞争性相互作用的响应曲线既是拮抗的（对于两种药物具有相反的作用）又是协同的（对于产生相同响应的两种药物）。另一方面，通过相反的机制（例如抑制k（in）加刺激k（out）），非竞争性作用于生产和耗散因子的药物的响应特征显示出净作用的显着变化并产生了明显的药物协同作用。通过ABEC值衡量的两种或多种药物联合使用的净间接应答概况可能看起来像“加和”，“拮抗”或“协同”，具体取决于剂量，其内在效力，相互作用的性质（竞争性或非竞争性），如以及它们的作用机制。与较早的经验方法相比，这些模型可能有助于以更理性和更机械的方式解释对两种药物的药理反应变化。