PHARMACOKINETIC-PHARMACODYNAMIC INTERACTION BETWEEN THE COMT INHIBITOR TOLCAPONE AND SINGLE-DOSE LEVODOPA

1 Single oral doses of the catechol-O-methyltransferase (COMT) inhibit or tolcapone (10-800 mg) or placebo were administered simultaneously w ith a dose of levodopa/benserazide 100/25 mg to seven sequential group s of six healthy male subjects in a two-way crossover study. 2 Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levod opa and 3-O-methyldopa (3-OMD) were determined in conjunction with COM T activity in erythrocytes. 3 The drug combination was well tolerated at all dose levels and there were no signs indicative of an increase i n dopaminergic stimulation. 4 Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose-de pendent decrease in the formation of 3-OMD. Tolcapone increased the ar ea under the concentration-time curve and elimination half-life of lev odopa. The maximum effects were obtained at a dose of about 200 mg whe n both parameters increased approximately twofold. The drug had no inf luence on the maximum concentration of levodopa. 5 Tolcapone was rapid ly absorbed and eliminated with, on average, a t(max) of 1.5 h and a t 1/2 of 2.3 h. The drug showed dose-proportional pharmacokinetics, in c ontrast to 3-O-methyltolcapone whose formation was relatively decrease d at higher doses. 6 Plasma concentrations of tolcapone correlated wit h inhibition of COMT activity in erythrocytes and suppression of 3-OMD levels, but not with changes in levodopa pharmacokinetics.