Studies on the pharmacokinetics of cisatracurium in anesthetized dogs: in vitro-in vivo correlations.

Cisatracurium undergoes primarily temperature and pH-dependent Hofmann elimination in humans. This study was conducted to describe the pharmacokinetics of cisatracurium in anesthetized dogs and determine whether its in vitro degradation rate in plasma is predictive of its in vivo elimination rate, as this is the case in humans. Nine dogs were anesthetized with pentobarbital and administered different bolus doses of cisatracurium in a randomized cross-over design. Arterial blood was collected at frequent intervals after each bolus injection. In vitro degradation rate (k(in vitro)) of cisatracurium was determined in each dog blank plasma. Plasma concentrations were determined by HPLC. Pharmacokinetic analyses were performed using two compartmental models assuming central or both central and peripheral elimination. Mean in vivo terminal elimination rate of cisatracurium (16.4 +/- 2.7 min) was twofold faster than mean in vitro degradation rate (32.9 +/- 3.7 min) in our dogs. Organ clearance was 6.12 +/- 1.69 mL/min.kg and accounted for 56 +/- 12% of the total body clearance. Apparent volume of distribution, an exit site-dependent parameter, averaged 212 or 184 mL/kg whether or not peripheral elimination was accounted for in the model. The in vitro rate of degradation in plasma is not of predictive value for the in vivo elimination rate of cisatracurium in anesthetized dogs. Organ clearance plays a more important role in the elimination of cisatracurium in dogs than in humans. Increased biliary excretion and/or presence of renal secretion are potential mechanisms that need to be explored.