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Potency of rapacuronium, its metabolite Org 9488, and other non-depolarizing muscle relaxants on recombinant muscle-type acetylcholine receptors: 33

Paul, M.; Fokt, R. M.; Kindler, C. H.; Dresser, M. J.; Yost, C. S.

European Journal of Anaesthesiology: November 2001 - Volume 18 - Issue - p 105–106
Abstracts from 7th International Neuromuscular Meeting, Belfast, June 2001
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Department of Anesthesia and Perioperative Care, Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143, USA

Introduction: Rapacuronium (RAP) is a recently introduced non-depolarizing muscle relaxant (NMB) characterized by fast onset and short duration of action. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking effects, which may become apparent after prolonged maintenance of relaxation with rapacuronium. The aim of this study was to compare the relative potency of RAP and ORG 9488, as well as Rocuronium (ROC), Vecuronium (VEC), Pancuronium (PAN), and D-Tubocurarine (D-TC) on fetal and adult isoforms of muscle-type achetylcholine receptors (n-AchR) using the Xenopus laevis oocyte expression system.

Methods: Nicotinic acetylcholine receptors (mouse fetal/γ-extrajunctional form and mouse adult/η-junctional form) were expressed separately in Xenopus oocytes by cytoplasmic injection of cRNAs encoding α, β, γ and δ subunits (fetal) or α, β, δ and η subunits (adult). Functional channels were activated with 10 μmol acetylcholine (ACh), alone and in solutions containing various concentrations of the NMBs. The resulting currents were recorded using a whole cell two-electrode voltage clamp technique. Data represent results from 4-6 oocytes for each NMB. Percentage inhibition of control-currents was plotted against drug concentrations (log mol). The concentration-response relations were fitted to a logistic function by means of an iterative, non-linear least-squares program, which derived the 50% inhibitory concentrations (IC50) and Hill coefficients [1].

Results: All tested NMBs reversibly inhibited ACh-activated inward currents in the tens of nmolar range (Table 1). Org 9488 was a more potent inhibitor than RAP. The rank order of potency for the adult n-AChR subtype was PAN>VEC>MIV>ROC>d-TC>ORG 9488>RAP. The fetal n-AChR was more potently inhibited than was the adult receptor type by RAP and Org 9488, and less inhibited by d-TC.

Table 1

Table 1

Conclusions: Org 9488 is an active metabolite of rapacuronium and appears in our experiments to be more potent than rapacuronium itself. This finding is consistent with modelled drug concentrations of the two compounds at the effect site in patients [2]. With the oocyte expression model, the rank order of potency of the tested NMBs for the η-nAChR correlates well with their known in vivo efficacy. Differences in potency at the two isoforms of the n-AChR, as observed here for RAP, ORG 9488, and d-TC have been reported previously for other steroidal NMBs [3]. These data provide further validation of the oocyte expression system for pharmacodynamic studies of NMBs.

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References:

1 Mol Pharmacol 1987; 32: 119-26.
2 Anesth Analg 1999; 88: 640-7.
3 Cell Mol Neurobiol 1997; 17: 35-50.
© 2001 European Society of Anaesthesiology