IMPORTANCE OF THE ORGAN-INDEPENDENT ELIMINATION OF CISATRACURIUM

Cisatracurium, one of 10 isomers of atracurium, undergoes pH and tempe rature-dependent Hofmann elimination in plasma and tissues. The cleara nce of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokin etic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constan ts, and the volume of the central compartment were obtained from the m odel fit. The elimination rate constant from the peripheral compartmen t could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 a nd 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal c learance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0 .86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL . min(-1). kg( -1) for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total bod y clearance. The organ-independent nature of the elimination of cisatr acurium was characterized by a relationship between steady-state volum e of distribution and total body clearance. The half-life is an indepe ndent variable and is not dependent on the total body clearance nor th e steady-state volume of distribution. Hofmann elimination is the pred ominant pathway for cisatracurium elimination in humans.