Effect of the gene dosage of CgammaP2C19 on diazepam metabolism in Chinese subjects.
OBJECTIVE
To determine whether the gene dosage of CYP2C19 affects the metabolism of diazepam and desmethyldiazepam in healthy Chinese subjects.


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 ml homozygotes (ml/ml), six ml heterozygotes (wt/ml), 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 ml/ml 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/ml 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/ml and wt/wt subjects (P < .01). As expected, the slowest mean clearance of diazepam was observed in the ml/ml subjects (2.8 +/- 0.9 mL/min) and the fastest in the wt/wt subjects (19.5 +/- 9.8 mL/min), with the wt/ml heterozygotes having an intermediate value (7.2 +/- 2.6 mL/min).


CONCLUSIONS
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.
Qin
X P
XP
Pharmacogenetics Research Institute, Hunan Medical University, China.
Xie
H G
HG
Wang
W
W
He
N
N
Huang
S L
SL
Xu
Z H
ZH
Ou-Yang
D S
DS
Wang
Y J
YJ
Zhou
H H
HH
D000328:Adult; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D044466:Asian People / Q000235:genetics*; D002681:China; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics*; D018628:Gene Dosage; D006207:Half-Life; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D003708:Nordazepam / Q000097:blood / Q000493:pharmacokinetics*; D010641:Phenotype; D012016:Reference Values
D014151:Anti-Anxiety Agents; D003708:Nordazepam; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D003975:Diazepam