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

Robert E. Black, BS, Ralph Gertler, MD, Peter M. C. Wright, MD, PhD, Mario T. Cancemi, BS, H. A. Tillmann Hein, MD, and Michael A. E. Ramsay, MD, FRCA

From the Department of Anesthesiology and Pain Management, Baylor University Medical Center, Dallas, Texas (Black, Cancemi, Hein, Ramsay); Department of Anesthesiology and Pain Management, The University of Texas Southwestern Medical Center, Dallas, Texas (Gertler, Hein, Ramsay); and the Department of Anesthesiology, University of California at San Francisco, San Francisco, California (Wright).

This study was supported in part by a grant from Organon Inc, West Orange, NJ.

Corresponding author: Michael A. E. Ramsay, MD, FRCA, Department of Anesthesiology and Pain Management, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, Texas 75246 (e-mail: docram@BaylorHealth.edu).

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.