瑞帕库溴铵（Org 9487）及其3-去乙酰代谢产物（Org 9488）的药代动力学及药代动力学-药效学关系

Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488).

作者信息

Schiere S, Proost J H, Schuringa M, Wierda J M

机构信息

Research Group for Experimental Anesthesiology and Clinical Pharmacology, University of Groningen, The Netherlands.

出版信息

Anesth Analg. 1999 Mar;88(3):640-7. doi: 10.1097/00000539-199903000-00032.

DOI:10.1097/00000539-199903000-00032

PMID:10072020

Abstract

UNLABELLED

Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that may become apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic behavior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK/PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were investigated in humans. Similar protocols were used for three study groups regarding the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyographically using the adductor pollicis muscle. The median clearance of rapacuronium was 7.28 mL x kg(-1) x min(-1) x with an excretion fraction in the urine of 6.2%. The clearance (studied in two groups) of Org 9488 was 1.28 and 1.06 mL x kg(-1) x min(-1) with an excretion fraction in the urine of 51.9% and 53.5%, respectively. The median rate constant of transport between plasma and the biophase of rapacuronium (0.449 min(-1)) is markedly larger than that for Org 9488 (0.105 min(-1)). The modeled concentration in the biophase at 50% effect as a measure of potency is higher for rapacuronium (4.70 microg/mL) than for Org 9488 (1.83 microg/mL). The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.

IMPLICATIONS

We investigated the concentration-time-effect relationship of the relaxant rapacuronium and the contribution of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect of rapacuronium are consistent with its rapid onset and short to intermediate duration. The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.

摘要

未标记

瑞帕库溴铵（Org 9487）是一种起效迅速、作用时间短至中等的肌肉松弛剂。其3 - 去乙酰代谢产物Org 9488也具有神经肌肉阻滞活性，在用瑞帕库溴铵长时间维持松弛后可能会显现出来。在本研究中，在人体中研究了该代谢产物的药代动力学行为（n = 7）以及瑞帕库溴铵（n = 10）和Org 9488（n = 7）的药代动力学/药效学（PK/PD）关系。三个研究组在麻醉技术、血液和尿液采样以及药代动力学和PK/PD分析方面使用了相似的方案。使用拇收肌通过肌电图测量作用时间进程。瑞帕库溴铵的中位清除率为7.28 mL·kg⁻¹·min⁻¹，尿排泄分数为6.2%。Org 9488的清除率（在两组中研究）分别为1.28和1.06 mL·kg⁻¹·min⁻¹，尿排泄分数分别为51.9%和53.5%。瑞帕库溴铵血浆与生物相之间转运的中位速率常数（0.449 min⁻¹）明显大于Org 9488（0.105 min⁻¹）。作为效能指标的生物相中50%效应时的模拟浓度，瑞帕库溴铵（4.70 μg/mL）高于Org 9488（1.83 μg/mL）。代谢产物较低的清除率将在使用瑞帕库溴铵维持期间逐渐延长神经肌肉阻滞的时间进程。