Objective: To evaluate fully the pharmacokinetics and pharmacodynamics of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT), after oral and intravenous administration.
Methods: Sixteen healthy male volunteers were given tolcapone in single doses of 200 mg orally and 50 mg intravenously, separated by a washout period of 7 days or more, in a single-center, open-label, randomized, cross-over study. Pharmacokinetic parameters were calculated using both compartmental and non-compartmental methods; pharmacodynamics were evaluated from erythrocyte COMT activity.
Results: After an initial lag time of 0.5 h, tolcapone was rapidly absorbed (peak plasma concentrations were reached within approximately 2 h) following either zero- or first-order absorption kinetics. The absolute bioavailability of an oral dose was approximately 60%. The volume of distribution was approximately 9 1, and the total clearance was approximately 71.h-l, resulting in a mean plasma half-life of 1.8 h. The degree of erythrocyte COMT inhibition was closely related to tolcapone plasma concentration; a rebound in COMT activity was observed after tolcapone withdrawal. Both oral and intravenous tolcapone were well tolerated.
Discussion: Because of its relatively low systemic clearance, tolcapone exhibits only a small degree of first-pass metabolism and a relatively good oral bioavailability, which explains the higher plasma concentrations and stronger COMT inhibition observed with tolcapone compared with entacapone, another COMT inhibitor. The pharmacokinetic and pharmacodynamic profile of tolcapone obtained in this study underlines the potential of the agent to be used as an adjunct to levodopa in the treatment of Parkinson's disease.