The tolerability, pharmacodynamics, and pharmacokinetics of BIA 3-202 (50 mg, 100 mg, and 200 mg twice daily and 200 mg thrice daily), a novel catechol-O-methyltransferase (COMT) inhibitor, were investigated in healthy volunteers. BIA 3-202 was administered to four sequential groups of 8 healthy male subjects under a double-blind, randomized, placebo-controlled design. Within each group, 2 subjects were randomized to treatment with placebo. Treatment duration was 9 days: single dose on the first and last days and twice or thrice daily on days 3 to 8. BIA 3-202 was well tolerated at all dose regimens tested. Median maximum plasma BIA 3-202 concentrations were attained at 0.5 to 2.5 hours postdose. Thereafter, concentrations declined with a t1/2 of approximately 2 to 4 hours. The increase in the extent of systemic exposure, as measured by AUC0-tau, was approximately proportional to the administered dose. Steady state of plasma BIA 3-202 concentrations occurred by day 4 in all dose groups. Less than 1% of the total dose administered was excreted in urine up to 48 hours postdose. BIA 3-202 markedly reduced soluble COMT (S-COMT) activity in erythrocytes, with maximum inhibition occurring at 1 to 2 hours postdose; enzyme activity returned to baseline levels by approximately 8 hours. Inhibition of S-COMT activity appeared to increase with increasing doses of BIA 3-202 on both day 1 and day 9. In conclusion, BIA 3-202 was well tolerated in all the oral multiple-dose regimens tested. BIA 3-202 was shown to inhibit S-COMT activity in erythrocytes, and its pharmacokinetics appeared to be linear (i.e., dose independent and time invariant).