Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects

Citation
Yp. Qin et al., Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects, CLIN PHARM, 66(6), 1999, pp. 642-646
Citations number
31
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
CLINICAL PHARMACOLOGY & THERAPEUTICS
ISSN journal
0009-9236 → ACNP
Volume
66
Issue
6
Year of publication
1999
Pages
642 - 646
Database
ISI
SICI code
0009-9236(199912)66:6<642:EOTGDO>2.0.ZU;2-W
Abstract
Objective: To determine whether the gene dosage of C Y P2C19 affects the me tabolism of diazepam and desmethyldiazepam in healthy Chinese subjects. Subjects and methods: Eighteen unrelated adult men were recruited for the s tudy from a total of 101 healthy Chinese volunteers who had been screened f or C Y P2C19 phenotype and genotype. All subjects received a single oral do se (5 mg) of diazepam, and the pharmacokinetics of diazepam and desmethyldi azepam were compared in six m1 homozygotes (m1/m1), six m1 heterozygotes (w t/m1), and six wild-type homozygotes (wt/wt). Results: The plasma elimination half-life values of diazepam (84.0 +/- 13.7 hours) and desmethyldiazepam (176.0 +/- 28.9 hours) in subjects of m1/m1 w ere significantly longer than those (62.9 +/- 9.8 hours for diazepam; 132.1 +/- 24.9 hours for desmethyldiazepam; both P < .01) in subjects of wt/wt o r those (20.0 +/- 10.8 hours for diazepam; 99.2 +/- 21.7 hours for desmethy ldiazepam; both P < .01) in subjects of wt/wt. A significant difference in the corresponding half-life values existed between the wt/m1 and wt/wt subj ects (P < .01). As expected, the slowest mean clearance of diazepam was obs erved in the m1/m1 subjects (2.8 +/- 0.9 ml/min) and the fastest in the wt/ wt subjects (19.5 +/- 9.8 mL/min), with the wt/m1 heterozygotes having an i ntermediate value (7.2 +/- 2.6 ml/min). Conclusion: The presence of a single-nucleotide polymorphism (G681A) of the C Y P2C19 gene cosegregates with the impaired metabolism of diazepam and d esmethyldiazepam among Chinese subjects in a gene-dosage effect manner.