Dutta S, Ebling W F
Department of Pharmaceutics, State University of New York at Buffalo, Amherst 14260, USA.
J Pharm Pharmacol. 1998 Jan;50(1):37-42. doi: 10.1111/j.2042-7158.1998.tb03302.x.
Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation is characterized by rapid onset and offset of effect after rapid intravenous administration and an effect-site equilibration half-life (t1/2kE0) of 1.7 min in rats. Paradoxically these characteristics are usually associated with relatively water-soluble anaesthetics. To test the influence of the formulation on propofol pharmacokinetics, effect-site equilibration kinetics and pharmacodynamics we performed a pharmacokinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with previous data obtained with rats receiving propofol in the emulsion formulation. Compared with the emulsion formulation the distribution volumes (VdC and VdSS) were significantly higher but the t1/2kE0 (2.0 min) was similar for the lipid-free formulation. The concentration-effect relationship was biphasic. Propofol effect-site concentrations required to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower, indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent characteristics of propofol's effect-time-course disappeared when the anaesthetic was administered in the lipid-free formulation. These results suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by modifying the pharmacokinetics or pharmacodynamics or both.
丙泊酚是一种高度亲脂性麻醉剂，其商业制剂为用于静脉注射的脂质乳剂（得普利麻）。该制剂的特点是静脉快速给药后起效和药效消失迅速，在大鼠中的效应室平衡半衰期（t1/2kE0）为1.7分钟。矛盾的是，这些特点通常与相对水溶性麻醉剂相关。为了测试制剂对丙泊酚药代动力学、效应室平衡动力学和药效学的影响，我们对长期植入仪器的大鼠给予无脂质制剂后进行了丙泊酚的药代动力学-药效学研究。在本报告中，我们展示了该研究的结果，并将这些结果与先前用接受乳剂制剂丙泊酚的大鼠获得的数据进行比较。与乳剂制剂相比，无脂质制剂的分布容积（VdC和VdSS）显著更高，但t1/2kE0（2.0分钟）相似。浓度-效应关系呈双相性。实现50%激活、峰值激活、峰值激活效应的50%抑制和最大抑制所需的丙泊酚效应室浓度显著更低，表明与乳剂制剂相比，无脂质制剂的表观稳态效能更高。当以无脂质制剂给药麻醉剂时，丙泊酚效应时程的短暂特征消失。这些结果表明，制剂的性质可通过改变药代动力学或药效学或两者来深刻影响静脉给药药物的临床特征。
