Klockowski P M, Levy G
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Amherst 14260.
J Pharm Sci. 1987 Jul;76(7):516-20. doi: 10.1002/jps.2600760705.
Computer simulations were performed to determine if the threshold dose of an infused drug (rather than the drug concentration in the biophase at onset of action) can be a suitable index for pharmacodynamic investigations as proposed by others. A two-compartment pharmacokinetic model with drug elimination from the central compartment was used for the simulations. Drug was administered into the central compartment by a constant-rate infusion, and concentrations in the central and peripheral compartments were calculated as a function of time. The pharmacologic effect was assumed to be reversible and to occur at a defined concentration (the effective concentration) in one or the other compartment. The dose required to produce an effective concentration (threshold dose) was determined as a function of infusion rate. The relationship between infusion rate and the dose required to produce an effective concentration in the peripheral compartment was found to be affected by drug distribution and elimination kinetics and by the effective concentration. The infusion rate-dose relationship showed a dose minimum at an infusion rate which others have designated as the "optimal dose rate" and have used for pharmacodynamic studies. No such minimum occurred for pharmacologic effects associated directly with drug concentrations in the central compartment. Since optimum dose rate and threshold dose are affected by both pharmacokinetic and pharmacodynamic alterations, it is concluded that this method (which avoids determination of drug concentrations) is not generally suitable for quantitative pharmacodynamic investigations.
进行了计算机模拟，以确定输注药物的阈值剂量（而非作用开始时生物相中的药物浓度）是否能如其他人所提议的那样，成为药效学研究的合适指标。模拟采用了一个具有从中央室消除药物功能的二室药代动力学模型。药物通过恒速输注进入中央室，并计算中央室和外周室中的浓度随时间的变化。假定药理效应是可逆的，且在一个或另一个室中在特定浓度（有效浓度）时发生。产生有效浓度所需的剂量（阈值剂量）被确定为输注速率的函数。发现外周室中产生有效浓度所需的输注速率与剂量之间的关系受药物分布和消除动力学以及有效浓度的影响。输注速率 - 剂量关系在一个输注速率处显示出剂量最小值，其他人已将该输注速率指定为“最佳剂量率”并用于药效学研究。与中央室中药物浓度直接相关的药理效应未出现这种最小值。由于最佳剂量率和阈值剂量受药代动力学和药效学改变的影响，得出的结论是，这种方法（避免了药物浓度的测定）通常不适用于定量药效学研究。
