Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

The effects of the cytochrome P450 (CYP)2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam were studied in 16 healthy male volunteers. The two mutated alleles (CYP2C192 and CYP2C193) causing absent CYP2C19 activity were identified by PCR-based restriction enzyme analysis. Five subjects had no mutated allele, five had one mutated allele, and six had two mutated alleles. Seven subjects were smokers, and nine were nonsmokers. The subjects received a single oral 4-mg dose of estazolam, and blood samplings and evaluation of psychomotor function were conducted up to 72 h after dosing. There was no significant difference among the groups with no, one, and two mutated alleles for the peak plasma concentration (145.2+/-36.5 vs. 142.1+/-33.6 vs. 113.2+/-29.7 ng/ml), area under the plasma concentration-time curve (0- infinity ) (4916.0+/-1276.4 vs. 4389.6+/-736.1 vs. 4047.3+/-613.8 ng x h/ml), apparent oral clearance (0.22+/-0.05 vs. 0.25+/-0.03 vs. 0.25+/-0.03 ml/min/kg), and elimination half-life (24.4+/-4.6 vs. 29.6+/-8.5 vs. 30.7+/-3.9 h). Similarly, none of the pharmacokinetic parameters was significantly different between the nonsmoker and smoker groups. Neither the number of mutated allele nor cigarette smoking affected the psychomotor function parameters significantly. The present study suggests that neither the CYP2C19 genotype nor cigarette smoking affects the single oral dose pharmacokinetics and pharmacodynamics of estazolam.