In an open, randomised, cross-over study we investigated the effect of a single 200 mg oral dose of entacapone, a novel catechol-O-methyltransferase (COMT) inhibitor, on the pharmacokinetics and metabolism of levodopa/carbidopa, and on the cardiovascular responses (blood pressure and pulse rate variation to standard stimuli) in eight parkinsonian patients. Entacapone significantly increased the mean area under the plasma concentration curve (AUC) of levodopa by 46%, from 3620 to 5280 h.ng.ml-1 and prolonged its elimination half-life (t1/2el) from 1.5 h to 2.0 h. The mean AUC of 3,4-dihydroxyphenylacetic acid (DOPAC), the monoamine oxidase-dependent metabolite of levodopa, was significantly increased from 122 to 343 h.micrograms.ml-1 by entacapone. A small decrease in the AUC of homovanillic acid (HVA), the COMT dependent metabolite of levodopa, was observed (from 455 to 303 h.ng.ml-1). Entacapone also decreased the excretion of HVA but not that of 3-methoxytyramine in the urine. Cardiovascular autonomic responses to sympathetic and parasympathetic stimuli were not changed by entacapone. We conclude that a single dose of entacapone moderately increases the AUC and prolongs the t1/2el of levodopa in man and that that does not affect cardiovascular autonomic regulation.