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). Conclusion: The present study suggests that the single-dose pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. [ABSTRACT FROM AUTHOR]