TY - JOUR

T1 - Pharmacokinetics and pharmacodynamics of mivacurium in patients phenotypically heterozygous for the usual and atypical plasma cholinesterase variants (UA)

AU - Østergaard, D.

AU - Viby-Mogensen, J.

AU - Rasmussen, S. N.

AU - Gätke, M. R.

AU - Pedersen, N. A.

AU - Skovgaard, L. T.

PY - 2003/11

Y1 - 2003/11

N2 - 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 O.1 mgkg-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 μg kg-1, respectively. The median (range) infusion rate was 3.7 μg 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. Conclusion: 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.

AB - 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 O.1 mgkg-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 μg kg-1, respectively. The median (range) infusion rate was 3.7 μg 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. Conclusion: 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.

KW - Butyrylcholinesterase

KW - Cholinesterase

KW - Cholinesterase variants

KW - Dose-response curves

KW - Enzymes

KW - Genetic factors

KW - Mivacurium

KW - Neuromuscular relaxants

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Pharmacology

KW - Pseudocholinesterase

KW - Stereo-isomers

U2 - 10.1046/j.1399-6576.2003.00243.x

DO - 10.1046/j.1399-6576.2003.00243.x

M3 - Journal article

C2 - 14616318

AN - SCOPUS:0344442826

VL - 47

SP - 1219

EP - 1225

JO - Acta Anaesthesiologica Scandinavica

JF - Acta Anaesthesiologica Scandinavica

SN - 0001-5172

IS - 10

ER -