The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype.
1. The disposition of diazepam and desmethyldiazepam was studied in 21 healthy male Chinese subjects who were phenotyped with mephenytoin. Four poor metabolizers (PM) were identified by phenotyping with mephenytoin and by genotyping for CYP2C19. 2. Serum diazepam and desmethyldiazepam concentrations were measured by high performance liquid chromatography in samples drawn up to 24 days after administration. 3. The plasma elimination half-lives of diazepam (100.8 +/- 32.3 h) and desmethyldiazepam (219.9 +/- 62.7 h) in PMs were significantly longer than those (34.7 +/- 23.0 h for diazepam, 103.1 +/- 25.9 h for desmethyldiazepam) of the 17 phenotyped extensive metabolizers (EM), and those (30.8 +/- 24.9 h for diazepam, 103.1 +/- 27.5 h for desmethyldiazepam) of the five genotyped EMs. 4. The mephenytoin S/R ratios were significantly correlated with the plasma half-lives of diazepam (r = 0.543, P < 0.05) and desmethyldiazepam (r = 0.522, P < 0.05), and with the clearance (r = -0.524, P < 0.05) of diazepam in 21 subjects. 5. These results are compatible with the conclusion that both diazepam and desmethyldiazepam are metabolized by cytochrome P450 CYP2C19 in the Chinese population. 6. The mephenytoin S/R ratios in nine EMs who drank alcohol frequently were significantly higher than those of seven EMs who were non-drinkers, but the plasma kinetics of diazepam and desmethyldiazepam were not significantly different between the two groups. The explanation for these finding is not clear.
Pharmacogenetics Research Institute, Human Medical University, Changsha, China.
J
J
Wan
H
H
Xia
N
N
He
Y Q
YQ
Lu
H H
HH
Zhou
D044466:Asian People / Q000235:genetics*; D002681:China; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000493:pharmacokinetics*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008617:Mephenytoin / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D010641:Phenotype; D011110:Polymorphism, Genetic
D003975:Diazepam; D008617:Mephenytoin