The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects.
OBJECTIVE
The aim of the present study was to investigate if subjects with one normal and one non-functional CYP2C19 allele (intermediate metabolizers; IMs) metabolized carisoprodol differently than individuals with two normal CYP2C19 alleles (extensive metabolizers; EMs) We also wanted to investigate whether the use of oral contraceptives influences the metabolism of carisoprodol in EMs and IMs. Impairing effects on psychomotor coordination and feelings of sedation were studied by comparing IMs with EMs following their ingestion of a single dose of 700 mg carisoprodol.


METHODS
Thirty-seven healthy Caucasian volunteers participated in the study, of whom 25 were not using any drugs known to interact with CYP2C19, including two poor metabolizers (PMs) (CYP2C19 *2/*2 or CYP2C19 *2 /*4), 11 IMs (CYP2C19 *1/*2 or CYP2C19 *1/*4) and 12 EMs (CYP2C19 *1/*1); the remaining 12 participants were six EMs and six IMs using oral contraceptives. A single oral dose of 700 mg of carisoprodol was given, and blood drug concentrations were followed for 11 h and 45 min. During this time period, different pharmacodynamic measurements were made.


RESULTS
IMs had a longer elimination half life (T(1/2)) (127 min; 95% confidence interval (CI) 95, 159) than EMs (96 min; 95% CI 84, 107) and a larger area under the concentration-time curve from 0 to infinity (AUC(0-infinity)) for carisoprodol (16.3 microg h ml(-1) ; 95% CI 11.9, 20.7) than EMs (11.3 microg h ml(-1) ; 95% CI 7.8, 14.8). The use of oral contraceptives was accompanied by larger AUC(0-infinity) for carisoprodol in both EMs (18.5 microg h ml(-1); 95% CI 10.7, 26.3) and IMs (26.0 microg h ml(-1) ; 95% CI 18.8, 33.2). EMs using oral contraceptives also had a longer T(1/2) (117 min; 95% CI 92, 143) and higher maximum carisoprodol concentration than EMs not using oral contraceptives. No significant differences in pharmacodynamic parameters were found between subjects in the different genotype groups or between users and non-users of oral contraceptives.


CONCLUSIONS
Subsequent to a single-dose administration of carisoprodol, the carisoprodol AUC was approximately 45% larger in CYP2C19 IMs than in EMs. The use of oral contraceptives increased the AUC by approximately 60% in both EMs and IMs. Despite these pharmacokinetic effects, no significant differences with respect to the CYP2C19 IM and EM genotypes were observed in the acute impairing effects of a single dose of carisoprodol.
Bramness
Jørgen G
JG
Norwegian Institute of Public Health, Division of Forensic Toxicology and Drug Abuse, P.O. Box 4404, Nydalen, 0403, Oslo, Norway. jorgen.bramness@fhi.no
Skurtveit
Svetlana
S
Gulliksen
Margaretha
M
Breilid
Harald
H
Steen
Vidar M
VM
Mørland
Jørg
J
D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002328:Carisoprodol / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003276:Contraceptives, Oral / Q000494:pharmacology*; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D013058:Mass Spectrometry; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*; D012016:Reference Values; D012680:Sensitivity and Specificity
D003276:Contraceptives, Oral; D009125:Muscle Relaxants, Central; D002328:Carisoprodol; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19