PHARMACOKINETICS OF MIVACURIUM ISOMERS AND THEIR METABOLITES IN HEALTHY-VOLUNTEERS AFTER INTRAVENOUS BOLUS ADMINISTRATION

Background: Previous studies report the pharmacokinetics of mivacurium isomers after an infusion using venous blood sampling, Although the e xtent of the mivacurium arterial-venous gradient is not known, the sam pling site is likely to influence mivacurium pharmacokinetic parameter s because the drug is rapidly metabolized as it traverses the circulat ion. The objectives of this study were (1) to determine the pharmacoki netics of mivacurium isomers in healthy persons after intravenous bolu s administration using intensive arterial blood sampling, and (2) to c haracterize the formation and elimination of mivacurium metabolites in human plasma. Methods: Eight persons classified as American Society o f Anesthesiologists physical status 1 or 2 who mere scheduled to under go elective surgery under balanced anesthesia received 0.15 mg/kg miva curium chloride as an intravenous bolus, Arterial blood samples were c ollected every 10 s during the first 2 min and at frequent intervals f or 4 h thereafter. Plasma concentrations of mivacurium isomers and the ir metabolites mere determined by two stereoselective high-performance liquid chromatographic methods coupled with fluorometric detection an d noncompartmental pharmacokinetic parameters. Results: Mean eliminati on half-lives of the trans-trans, cis-trans, and cis-cis isomers were 2.4, 2, and 28.5 min, respectively with corresponding mean plasma clea rances of 29.2, 45.7, and 6.7 ml . min(-1) . kg(-1). The volumes of di stribution at steady state of the trans-trans, cis-trans, and cis-cis isomers were 0.047, 0.054, and 0.189 l/kg, respectively. Plasma concen trations of monoester and alcohol metabolites peaked 25 s (median) aft er mivacurium injection, with half-lives in the range of 90 min, excep t for the cis alcohol metabolite, which was only negligibly and transi ently formed. Conclusions: Substantial hydrolysis of mivacurium isomer s by cholinesterases mas confirmed by the rapid appearance of mivacuri um metabolites in plasma. The Intensive arterial sampling proved to be critical for tile trans-trans and cis-trans isomers because the area under the curve between 0 and 2 min accounted for 75% and 86% of the t otal, respectively.