Importance of the organ-independent elimination of cisatracurium.
Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic 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 constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 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 clearance 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 body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans.
Division of Clinical Pharmacology, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
D F
DF
Kisor
V D
VD
Schmith
W A
WA
Wargin
C A
CA
Lien
E
E
Ornstein
D R
DR
Cook
D000328:Adult; D001279:Atracurium / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007546:Isoquinolines / Q000097:blood / Q000652:urine; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D009466:Neuromuscular Blocking Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013696:Temperature; D014018:Tissue Distribution
D007546:Isoquinolines; D009466:Neuromuscular Blocking Agents; D001279:Atracurium; C001522:laudanosine; C101584:cisatracurium