Pharmacokinetics and pharmacodynamics of mivacurium in patients phenotypically heterozygous for the usual and atypical plasma cholinesterase variants (UA).
BACKGROUND
Mivacurium is hydrolyzed by plasma cholinesterase (pChe). The purpose of this study was to evaluate the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium in patients phenotypically heterozygous for the usual and the atypical pChe variant (UA).


METHODS
Thirty-two patients were included in a dose-response study, in which the patients received one of four doses of mivacurium. An additional bolus dose of mivacurium, to a total of 0.1 mg kg-1, was given followed by a continuous infusion adjusted to maintain 91-99% neuromuscular block. The times to different levels of recovery following the infusion were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Twelve of the patients with an estimated duration of anaesthesia of more than 90 min were (randomly) selected for the pharmacokinetic part of the study. Venous samples were taken for determination of the three isomers of mivacurium. These results were compared with results from a previous study in phenotypically normal patients (UU).


RESULTS
The estimated ED50 and ED95 were 24 and 69 microg kg-1, respectively. The median (range) infusion rate was 3.7 microg kg-1 min-1 (1.2-2.9) and the time to a TOF ratio of 0.7 was 29.8 min (16.1-44.8). The median clearances of the cis-cis, cis-trans and trans-trans isomers were 3.7, 29 and 28 ml kg-1 min-1, respectively. The elimination half-lives of the isomers were 45, 6.7 and 6.3 min, respectively.


CONCLUSIONS
In patients heterozygous for the usual and the atypical variant (UA), the potency of mivacurium is higher, the infusion requirements lower and the rate of spontaneous recovery prolonged, compared with phenotypically normal patients. The clearances of the active isomers are significantly lower and the elimination half-lives longer in heterozygous patients than in phenotypically normal patients (UU). The pharmacokinetics of the inactive cis-cis isomer was not affected.
Østergaard
D
D
Department of Anaesthesia and Intensive Care, Danish Cholinesterase Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark. Dooe@herlevhosp.kbhamt.dk
Viby-Mogensen
J
J
Rasmussen
S N
SN
Gätke
M R
MR
Pedersen
N A
NA
Skovgaard
L T
LT
D000293:Adolescent; D000328:Adult; D000368:Aged; D002802:Cholinesterases / Q000097:blood / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006579:Heterozygote; D006801:Humans; D007536:Isomerism; D007546:Isoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D000077590:Mivacurium; D019148:Neuromuscular Blockade; D003473:Neuromuscular Nondepolarizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010641:Phenotype
D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D000077590:Mivacurium; D002802:Cholinesterases