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

Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromus cular-blocking activity that. may became apparent after prolonged maintenan ce of relaxation with rapacuronium. In this study, the pharmacokinetic beha vior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK /PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were invest igated in humans. Similar protocols were used for three study groups regard ing the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyograph ically using the adductor pollicis muscle. The median clearance of rapacuro nium 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 128 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 f or Org 9488 (0.105 min(-1)). The modeled concentration in the biophase at 5 0% effect as a measure of potency is higher for rapacuronium (4.70 mu g/mL) than for Org 9488 (1.83 mu g/mL). The lower clearance of the metabolite wi ll gradually prolong the time course of the neuromuscular blockade during m aintenance with rapacuronium. Implications: We investigated the concentrati on-time-effect relationship of the relaxant rapacuronium and the contributi on of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect o f rapacuronium are consistent with its rapid onset and short to intermediat e duration. The lower clearance of the metabolite will gradually prolong th e time course of the neuromuscular blockade during maintenance with rapacur onium.