Wierda J M, Proost J H
Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Hospital, Groningen Institute for Drug Studies (GIDS), The Netherlands.
Eur J Anaesthesiol Suppl. 1995 Sep;11:45-54.
Several new steroidal non-depolarizing muscle relaxants have been synthesized and tested in humans recently. Results from these studies suggest that the differences in time-course of action between these compounds are mainly, if not totally, related to differences in biodisposition. Biodisposition, in turn, is determined largely by the physico-chemical characteristics of the drug, such as degree of lipophilicity and protein binding. The various pharmacodynamic and pharmacokinetic variables of a series of structurally related steroidal relaxants, varying in the ester substituent at the 17th position of the androstane skeleton, have been related to the degree of lipophilicity. Significant positive relationships could be shown between lipophilicity (logP at pH 7.4) and, among other things, potency (ED90), effective concentration (EC50), unbound plasma clearance (CLupl) and rate constant of transport between plasma and biophase (ke0). The aforementioned relationships between lipophilicity and pharmacokinetic variables resulted in significant inverse relationships between lipophilicity and time course parameters, such as onset time and duration of neuromuscular blocking effects. It is concluded that changes in the molecular structure of steroidal relaxants which enhance lipophilicity coincide with a decrease of (intrinsic) potency and a shorter time course of action. Protein binding appears to be of minor importance for the biodisposition and time course characteristics, since there were only small differences in degree of protein binding between most of the investigated compounds. However, the surprisingly fast initial rate of block development observed with rocuronium may in part result from its relatively high unbound fraction in plasma.
最近已合成了几种新型甾体非去极化肌松药并在人体进行了测试。这些研究结果表明，这些化合物作用时程的差异即使不是完全，也主要与生物处置的差异有关。而生物处置在很大程度上又由药物的物理化学特性决定，如亲脂性程度和蛋白结合情况。一系列结构相关的甾体肌松药，其雄甾烷骨架第17位酯取代基不同，各种药效学和药代动力学变量已与亲脂性程度相关联。亲脂性（pH 7.4时的logP）与效价（ED90）、有效浓度（EC50）、非结合血浆清除率（CLupl）以及血浆与生物相之间的转运速率常数（ke0）等之间可呈现显著的正相关关系。上述亲脂性与药代动力学变量之间的关系导致亲脂性与时间过程参数（如起效时间和神经肌肉阻滞作用持续时间）之间呈现显著的负相关关系。得出的结论是，甾体肌松药分子结构中增强亲脂性的变化与（内在）效价降低和作用时程缩短相吻合。蛋白结合对生物处置和时间过程特征似乎不太重要，因为大多数研究化合物之间的蛋白结合程度只有很小差异。然而，罗库溴铵观察到的令人惊讶的快速初始阻滞发展速率可能部分归因于其在血浆中相对较高的非结合分数。
