EFFECT OF ENTACAPONE, A COMT INHIBITOR, ON THE PHARMACOKINETICS AND METABOLISM OF LEVODOPA AFTER ADMINISTRATION OF CONTROLLED-RELEASE LEVODOPA-CARBIDOPA IN VOLUNTEERS

We studied the effect of entacapone, a catechol-O-methyltransferase (C OMT) inhibitor, on the pharmacokinetics and metabolism of levodopa aft er administration of a controlled-release (CR) levodopa-carbidopa prep aration (Sinemet CR) in an open, randomized trial in 12 healthy male v olunteers. The inhibition of soluble COMT (S-COMT) in red blood cells (RBCs) was also measured. Single graded doses of entacapone (100-800 m g) were administered concomitant with a single oral dose of CR levodop a, or CR levodopa was given without entacapone (control treatment), at least 1 week apart. Plasma concentrations of levodopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (H VA), carbidopa, and entacapone were determined for pharmacokinetic cal culations. Entacapone decreased dose-dependently the activity of S-COM T in RBCs with a maximal inhibition of 66% after the highest dose (800 mg). Entacapone increased the area under the plasma concentration-tim e curve (AUG) of levodopa; the increase was highest (33%) after the 40 0-mg dose. Entacapone did not influence time to maximal concentration (T-max) of levodopa. Entacapone was absorbed faster than levodopa from the CR preparation. The AUCs of 3-OMD and HVA decreased and that of D OPAC increased dose-dependently after entacapone, maximally by 69, 38, and 74%, respectively. Higher doses of entacapone (400 mg and 800 mg) decreased the AUG, but not T-max of carbidopa. Over the dose range st udied, entacapone was well tolerated. Entacapone is an effective COMT inhibitor. It improves the pharmacokinetic profile of levodopa when us ed in combination with a CR levodopa preparation, as it does with a st andard levodopa preparation. The results justify further clinical stud ies with entacapone in combination with CR preparations of levodopa.