THE PHARMACODYNAMICS AND PHARMACOKINETICS OF THE METABOLITE 3-DESACETYLVECURONIUM (ORG-7268) AND ITS PARENT COMPOUND, VECURONIUM, IN HUMAN VOLUNTEERS

The pharmacology of 3-desacetylvecuronium, the principal metabolite of vecuronium, was investigated. We studied 12 healthy volunteers, each on two occasions. First they received 3-desacetylvecuronium alone and then, on a later occasion, vecuronium. Six subjects received a large d ose of each drug (pharmacokinetic study), the remaining six received a small dose (pharmacodynamic study). Drug concentrations in plasma and urine were measured using capillary gas chromatography. Neuromuscular block was assessed by measuring force of contraction of the adductor pollicis. Drug plasma concentration vs. time and neuromuscular effect data were analyzed by nonlinear mixed-effects modeling. 3-Desacetylvec uronium, compared with vecuronium (median, range in parentheses), had a smaller plasma clearance, 3.51 (2.11-6.57) vs. 5.39 (5.04-7.19) ml.k g(-1) min(-1); a larger steady-state distribution volume, 254 (215-410 ) vs. 152 (111-170) ml.kg(-1); a longer terminal elimination half-life 116 (44-672) vs. 34 (25-61) min and a longer mean residence time, 67 (42-145) vs. 26 (18-32) min (P < .05). Renal clearances of 3-desacetyl vecuronium and vecuronium were 0.85 (0.15-1.24) and 0.58 (0.16-0.66) m l.kg(-1).min(-1), respectively (P < .05). Conversion to 3-desacetylvec uronium accounted for 12% of vecuronium's clearance. Concentrations of 3-desacetylvecuronium and vecuronium that produced 50% neuromuscular block were 123 (109-154) and 102 (71-123) ng.ml(-1), respectively (P < .05). 3-Desacetylvecuronium is a potent neuromuscular blocking drug a nd may be responsible for episodes of prolonged paralysis after long-t erm administration of vecuronium to patients in intensive care units.