Stereoselective in vitro degradation pattern of mivacurium in human plasma.

ABSTRACT

BACKGROUND: Mivacurium is a mixture of three isomers, two of which are rapidly broken down in vivo by plasma cholinesterases. This study investigates the stereospecificity of mivacurium in vitro degradation to determine if it accounts for its in vivo behaviour. METHODS: The in vitro rate of degradation of each isomer of mivacurium and the in vitro rate of formation of their primary (monoesters and alcohols) and secondary (alcohols) metabolites were examined using human plasma from six healthy volunteers. The in vitro rate of degradation of the monoester metabolites was also assessed. All these determinations were made using a stereospecific high-performance liquid chromatography assay. RESULTS: The in vitro rate of disappearance of the two active isomers of mivacurium was very rapid, with mean values for the trans trans and cis trans isomers of 0.803 and 0.921 min(-1) respectively. These values are twofold faster than published in vivo data. The in vitro rate of disappearance was much slower for the cis cis isomer, with a mean value of 0.0106 min(-1). The cis trans isomer was converted exclusively to cis monoester and trans alcohol, while only metabolites in the trans and cis configuration were found for the trans trans and cis cis isomers respectively. Mean in vitro rates of disappearance for the trans and cis monoester were 0.00750 and 0.000633 min(-1) respectively. CONCLUSIONS: The in vitro rates of hydrolysis of the active isomers of mivacurium confirm that plasma cholinesterases play a major role in their in vivo degradation, but that in vivo elimination is slowed by extravascular distribution. Mivacurium hydrolysis is stereoselective, the ester group in the trans configuration being more accessible to enzymatic attack. This stereoselective pattern, along with the relatively slow breakdown of the cis cis isomer, sheds light on the in vivo disposition of the cis alcohol metabolite.