A KINETIC AND DYNAMIC STUDY OF ORAL ALPRAZOLAM WITH AND WITHOUT ERYTHROMYCIN IN HUMANS - IN-VIVO EVIDENCE FOR THE INVOLVEMENT OF CYP3A4 IN ALPRAZOLAM METABOLISM

Objective: To assess the possible involvement of CYP3A4 in the metabol ism of alprazolam in vivo. Method: Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, p lacebo-erythromycin or erythromycin-placebo, with an at least 6-week w ashout period between the two trial phases. Each volunteer received 40 0 mg erythromycin or matched placebo given orally three times a day fo r 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8, Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at ea ch time of blood samplings with use of the Digit Symbol Substitution T est, visual analog scale, and Udvalg for kliniske undersogelser side e ffect rating scale. Results: Erythromycin significantly (p < 0.001) in creased the area under the plasma concentration-time curves (200 +/- 4 3 versus 322 +/- 49 ng hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and pro longed the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 ho urs) of alprazolam. However, any psychomotor function variables did no t differ significantly between the erythromycin and placebo trial phas es. Conclusion: This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo e vidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of alprazolam by erythromycin does not result in the ph armacodynamic change of this triazolobenzodiazepine, at least after si ngle dosing.