Pharmacokinetic analysis of rapacuronium and its metabolite during liver transplantation: an assessment of its potential as a pharmacodynamic probe.

The liver extracts aminosteroidal neuromuscular blocking drugs. We hypothesized that the duration of action of these drugs might provide a pharmacodynamic probe for assessing graft function during orthotopic liver transplantation. The pharmacokinetics of rapacuronium and its active metabolite, ORG 9488, were prospectively studied in 11 patients. Rapacuronium (1.5 mg/kg) was administered at induction of anesthesia, 2 minutes after clamping the portal vein, and 5 minutes after reperfusion of the new graft. Blood samples were drawn at intervals, and an independent laboratory analyzed plasma for both rapacuronium and ORG 9488. Rapacuronium's pharmacokinetics were characterized for 3 stages of the transplant using NONMEM software to construct mixed-effects compartmental models. Rapacuronium plasma clearance during the first stage of orthotopic liver transplantation was 7.25 mL/kg/min. Clearance decreased by only 44% during the anhepatic stage, to 3.91 mL/kg/min, and remained decreased after reperfusion. This effect suggests that an alternate clearance pathway exists. The clearance for ORG 9488 was 13.5 mL/kg/min during the paleohepatic and anhepatic stages, but it decreased 83% on reperfusion, suggesting accumulation after reperfusion. This pharmacokinetic analysis suggests that rapacuronium may not be suitable for use as a pharmacodynamic probe.