Influence of alaproclate on antipyrine metabolite formation in man

Alaproclate, a selective serotonin reuptake inhibitor, presently undergoing clinical trial for the treatment of major depressive disorders, has been shown to inhibit hexobarbital metabolism in mice. In the present study the influence of oral alaproclate on the total plasma clearance of antipyrine and on the formation of its metabolites was investigated in 10 healthy volunteers. The peak level of alaproclate was reached after about 1.5 h, and after a distribution phase, its plasma elimination half-life was between 3.0 and 3.5 h. Antipyrine tests were performed before treatment, during the first four doses and after the seventh dose of alaproclate 200 mg/day. During treatment, total plasma antipyrine clearance and the clearance for production of all antipyrine metabolites were reduced by 30%, indicating non-selective inhibition of oxidative drug-metabolizing enzyme activity in man by alaproclate. After the last dose of alaproclate, antipyrine plasma clearance and the clearance to its metabolites returned to control values. In order to allow more detailed evaluation of the results, the time course of the clearances for production of metabolites was investigated. This revealed that the extent of inhibition of metabolite formation by alaproclate was dependent on the plasma alaproclate level, indicating a rapidly reversible inhibition.