Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity.
OBJECTIVE
To examine the effect of cytochrome P450 (CYP) 2C19 activity on the single-dose pharmacokinetics and pharmacodynamics of etizolam.


METHODS
The subjects were 21 healthy Japanese volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by a polymerase chain reaction method. Twelve subjects were extensive metabolizers (EMs) with no or one mutated allele, and nine subjects were poor metabolizers (PMs) with two mutated alleles. The subjects received a single oral 1-mg dose of etizolam, and blood samplings and evaluation of psychomotor function were conducted up to 24 h after dosing.


RESULTS
The PMs had significantly larger total area under the plasma concentration-time curve (287+/-74 vs 178+/-122 ng.h/ml, p<0.05) and longer elimination half-life (14.8+/-4.2 vs 10.5+/-3.9 h, p<0.05) of etizolam than the EMs. The area under the score-time curve from 0 to 8 h of the Stanford Sleepiness Scale was significantly larger in the PMs than in EMs (28.9+/-5.2 vs 22.9+/-6.9 score.h, p<0.05).


CONCLUSIONS
The present study suggests that the single-dose pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity.
Fukasawa
T
T
Department of Psychiatry, Yamagata University School of Medicine, 990-9585 Yamagata, Japan. tfukasaw@med.id.yamagata-u.ac.jp
Yasui-Furukori
N
N
Suzuki
A
A
Inoue
Y
Y
Tateishi
T
T
Otani
K
K
D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D003975:Diazepam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D007564:Japan; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D011597:Psychomotor Performance / Q000187:drug effects*; D014149:Tranquilizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology
D014149:Tranquilizing Agents; C044610:etizolam; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D003975:Diazepam