PHARMACOKINETICS OF THE 3 ISOMERS OF MIVACURIUM AND PHARMACODYNAMICS OF THE CHIRAL MIXTURE IN HEPATIC CIRRHOSIS

We have studied the pharmokinetics of cis-trans, trans-trans and cis-cis mivacurium in 10 healthy subjects and 11 patients with mild or moderate hepatic cirrhosis, during nitrous oxide-oxygen-isoflurane anaesthesia. Mivacurium 15 mu g kg(-1) min(-1) was infused for 10 min (total dose 0.15 mg kg(-1)) and the plasma concentration of the three isomers measured at regular intervals for 190 min. The electromyographic response to the drug was also measured. Compartmental analysis of the resulting isomer profiles was undertaken: one- and two-compartment models were fitted to derive clearance, volume of distribution and half-life. Clearance of the cis-trans and trans-trans isomers was reduced significantly in the cirrhotic compared with the healthy group: cis-trans (median (range)) 44 (15-121) ml kg(-1) min(-1) vs 95 (57-213) ml kg(-1) min(-1) (P < 0.05); trans-trans 32 (12-64) ml kg(-1) min(-1) vs 70 (34-101) ml kg(-1) min(-1) (P < 0.05). The difference in the clearance of the cis-cis isomer in the cirrhotic (4.2 (2.9-12.1) ml kg(-1) min(-1) compared with the healthy group (5.2 (2.9-8.9) ml kg(-1) min(-1)) was not significant with this sample size. Clearance of each isomer correlated significantly with plasma cholinesterase activity: cis-trans r = 0.73, P < 0.001; trans-trans r = 0.69, P < 0.001; cis-cis r = 0.48, P < 0.05. Terminal half-life was prolonged significantly for the cis-trans and trans-trans isomers in the cirrhotic patients compared with the healthy subjects: cis-trans 2.5 (1.3-64.6) min vs 1.5 (0.7-2.2) min (P < 0.05); trans-trans 11.1 (2.8-36.9) min vs 2.3 (1.2-7.8) min (P < 0.001), but was not statistically significant for the cis-cis isomer: 60.8 (8.7-155) min vs 50.3 (12.6-237) min. Volume of distribution was similar for all three isomers in the healthy and cirrhotic groups. Onset and recovery from neuromuscular block were slower in the cirrhotic compared with the healthy group: time to 90% depression of T1/T0 6.8 (5.8-11.5) min vs 5.9 (5.3-10.3) min (P < 0.05); recovery index (25-75% recovery of T1/T0) 11.8 (5.6-26.3) min vs 7.4 (4.7-9.6) min (P < 0.01). There was a significant negative correlation between all recovery variables and plasma cholinesterase activity.