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

1 Single oral doses of the catechol-O-methyltransferase (COMT) inhibitor tolcapone (10-800 mg) or placebo were administered simultaneously with a dose of levodopa/benserazide 100/25 mg to seven sequential groups of six healthy male subjects in a two-way crossover study. 2 Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa (3-OMD) were determined in conjunction with COMT activity in erythrocytes. 3 The drug combination was well tolerated at all dose levels and there were no signs indicative of an increase in dopaminergic stimulation. 4 Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose-dependent decrease in the formation of 3-OMD. Tolcapone increased the area under the concentration-time curve and elimination half-life of levodopa. The maximum effects were obtained at a dose of about 200 mg when both parameters increased approximately twofold. The drug had no influence on the maximum concentration of levodopa. 5 Tolcapone was rapidly absorbed and eliminated with, on average, a t(max) of 1.5 h and a t1/2 of 2.3 h. The drug showed dose-proportional pharmacokinetics, in contrast to 3-O-methyltolcapone whose formation was relatively decreased at higher doses. 6 Plasma concentrations of tolcapone correlated with inhibition of COMT activity in erythrocytes and suppression of 3-OMD levels, but not with changes in levodopa pharmacokinetics.