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

Abstract

Objective To determine whether the gene dosage of CYP2C19 affects the metabolism of diazepam and desmethyldiazepam in healthy Chinese subjects. Subjects and Methods Eighteen unrelated adult men were recruited for the study from a total of 101 healthy Chinese volunteers who had been screened for CYP2C19 phenotype and genotype. All subjects received a single oral dose (5 mg) of diazepam, and the pharmacokinetics of diazepam and desmethyldiazepam were compared in six m1 homozygotes (m1/m1), six m1 heterozygotes (wt/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 were 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/m1 or those (20.0 ± 10.8 hours for diazepam; 99.2 ± 21.7 hours for desmethyldiazepam; 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 subjects (P < .01). As expected, the slowest mean clearance of diazepam was observed 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 intermediate value (7.2 ± 2.6 mL/min). Conclusion The presence of a single-nucleotide polymorphism (G681A) of the CYP2C19 gene cosegregates with the impaired metabolism of diazepam and desmethyldiazepam among Chinese subjects in a gene-dosage effect manner. Clinical Pharmacology & Therapeutics (1999) 66, 642–646; doi: 10.1053/cp.1999.v66.103379001