EFFECT OF ENTACAPONE, A COMT INHIBITOR, ON THE PHARMACOKINETICS OF LEVODOPA AND ON CARDIOVASCULAR-RESPONSES IN PATIENTS WITH PARKINSONS-DISEASE

In an open, randomised, cross-over study we investigated the effect of a single 200 mg oral dose of entacapone, a novel catechol-O-methyltra nsferase (COMT) inhibitor, on the pharmacokinetics and metabolism of l evodopa/carbidopa, and on the cardiovascular responses (blood pressure and pulse rate variation to standard stimuli) in eight parkinsonian p atients. Entacapone significantly increased the mean area under the pl asma 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), t he monoamine oxidase-dependent metabolite of levodopa, was significant ly increased from 122 to 343 h . mug . ml-1 by entacapone. A small dec rease in the AUC of homovanillic acid (HVA), the COMT dependent metabo lite of levodopa, was observed (from 455 to 303 h . ng . ml-1). Entaca pone also decreased the excretion of HVA but not that of 3-methoxytyra mine in the urine. Cardiovascular autonomic responses to sympathetic a nd parasympathetic stimuli were not changed by entacapone. We conclude that a single dose of entacapone moderately increases the AUC and pro longs the t1/2el of levodopa in man and that that does not affect card iovascular autonomic regulation.