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.