title: Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects?
abstract: Carisoprodol is metabolized to meprobamate by the cytochrome P450 enzyme CYP2C19, encoded by the polymorphic CYP2C19 gene. Most studies on carisoprodol metabolism have been carried out on individuals phenotyped for CYP2C19 activity using the probe drug S-mephenytoin. We aimed to investigate whether the ratio of carisoprodol to meprobamate in a 'real life' setting could be predicted by CYP2C19 genotype or, more specifically, if high carisoprodol : meprobamate ratios in drugged drivers could be ascribed to the presence of mutant CYP2C19 alleles. From original material comprising 358 blood samples from apprehended drivers, two polarized groups were selected; a high-ratio group of 11 subjects where the carisoprodol : meprobamate ratio was >1 and a low-ratio control group of 23 subjects where the ratio was <0.31. Genotyping was carried out for the CYP2C19*2, CYP2C19*3 and CYP2C19*4 alleles. DNA samples from 94 healthy blood donors were used as reference material. The number of mutant alleles in the high-ratio and low-ratio groups was significantly higher and lower, respectively, than in the reference material. The increased number of mutant alleles in the high-ratio group was not due to the presence of many poor metabolizers, but to a high number of heterozygous individuals with the genotype CYP2C19*1/*2. This result indicates a gene dosage effect where the carisoprodol : meprobamate ratio reflects the number of active CYP2C19 alleles. The metabolism of carisoprodol to meprobamate is dependent on CYP2C19 genotype. Heterozygous individuals with the CYP2C19*1/*2 genotype have a reduced capacity for metabolizing carisoprodol, and should probably be regarded as intermediate metabolizers of this drug.
authors.affiliation: Norwegian Institute of Public Health, Division of Forensic Toxicology and Drug Abuse, Oslo, Norway. jorgen.bramness@labmed.uio.no
authors.forename: Jørgen G
authors.initials: JG
authors.lastname: Bramness
authors.forename: Svetlana
authors.initials: S
authors.lastname: Skurtveit
authors.forename: Lars
authors.initials: L
authors.lastname: Fauske
authors.forename: Merete
authors.initials: M
authors.lastname: Grung
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Jørg
authors.initials: J
authors.lastname: Mørland
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
mesh_terms: D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D002328:Carisoprodol / Q000097:blood / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008620:Meprobamate / Q000097:blood / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D012016:Reference Values; D012189:Retrospective Studies; D019966:Substance-Related Disorders / Q000097:blood / Q000150:complications / Q000378:metabolism
chemical_list: D002328:Carisoprodol; D008620:Meprobamate; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19