title: CYP3A4 and CYP2C19 genetic polymorphisms and zolpidem metabolism in the Chinese Han population: a pilot study.
abstract: Zolpidem (ZPD) is an imidazopyridine hypnotic and little is known about the pharmacogenetics of ZPD. Our objective was to evaluate inter-individual genetic variation in conjunction with metabolic ratios of ZPD found in a toxicological analysis. Healthy individuals (n=300) were genotyped for CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP1A2 by allele-specific primer extension followed by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Twenty-four Chinese volunteers were chosen and divided into the following four groups (n=6/group): group 1: CYP3A4*18 (wild-type, W), CYP2C19*2 (W); group 2: CYP3A4*18 (mutant, M), CYP2C19*2 (W); group 3: CYP3A4*18 (W), CYP2C19*2 (M); and group 4: CYP3A4*18 (M), CYP2C19*2 (M). ZPD and its major metabolites zolpidem 6-carboxylic acid (ZCA) and zolpidem phenyl-4-carboxylic acid (ZPCA) were determined after oral administration of ZPD (10mg), using an UPLC-MS/MS method. Positive correlations between CYP3A4 and CYP2C19 alleles and ZPD metabolism were found. The results of this study show that CYP3A4*18 increases CYP3A4 activity while CYP2C19*2 reduces CYP2C19 activity; the latter mutation is associated with the poor metabolism of ZPD in the Chinese Han population. The results also suggest that genetic factors play a major role in the metabolism of individual drugs with implications for both forensic science and clinical pharmacogenetics.
authors.affiliation: Shanghai Key Laboratory of Forensic Medicine, Department of Forensic Toxicology, Institute of Forensic Science, Ministry of Justice, Guangfu Xi Road 1347, Shanghai 200063, PR China. minshensfjd@hotmail.com
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Ping
authors.initials: P
authors.lastname: Xiang
mesh_terms: D000483:Alleles; D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002681:China; D002853:Chromatography, Liquid; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D053593:Forensic Toxicology; D005838:Genotype; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013058:Mass Spectrometry / Q000379:methods; D009154:Mutation; D010597:Pharmacogenetics; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000077334:Zolpidem
chemical_list: D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human