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Anesth Analg 1999;88:640
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

Pharmacokinetics and Pharmacokinetic-Dynamic Relationship Between Rapacuronium (Org 9487) and Its 3-Desacetyl Metabolite (Org 9488)

Sjouke Schiere, MD, Johannes H. Proost, PharmD, PhD, Marriët Schuringa, MD, and J. Mark K. H. Wierda, MD, PhD

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

Address correspondence and reprint requests to Dr. J. M. K. H. Wierda, Department of Anesthesiology, University Hospital, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Address e-mail to j.m.k.h.wierda{at}med.rug.nl

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 · kg-1 · min-1 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 · kg-1 · 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 µg/mL) than for Org 9488 (1.83 µg/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.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 1999 by the International Anesthesia Research Society.