EFFECT OF ONE MONTHS TREATMENT WITH PERIPHERALLY ACTING CATECHOL-O-METHYLTRANSFERASE INHIBITOR, ENTACAPONE, ON PHARMACOKINETICS AND MOTOR RESPONSE TO LEVODOPA IN ADVANCED PARKINSONIAN-PATIENTS

Twelve parkinsonian patients with levodopa-related end-of-dose fluctua tions in disability were studied in an open-label trial to examine the effects of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on pharmacokinetics and metabolism of levodopa and on clinical response to levodopa after a single dose and after 4 weeks' m edication with entacapone. The clinical response was assessed with con tinuous monitoring using the motor part of Unified Parkinson's Disease Rating Scale. Entacapone increased statistically significantly the me an area under the plasma concentration-time curve (AUC) of levodopa by 29% after a single dose and by 21% after 4 weeks' administration, wit hout affecting other pharmacokinetic parameters of levodopa, The AUC o f 3-O-methyldopa decreased by 45% and AUC of homovanillic acid by 21% after 4 weeks' dosing with entacapone. The duration of motor response to levodopa increased significantly from 2.3 h to 3.2 h (i.e., by 39%) after a single dose and to 3.4 h (i.e., by 48%) after 4 weeks' medica tion with entacapone. The magnitude of clinical response remained unch anged, but peak latency of motor response was prolonged after 4 weeks' medication. The duration and magnitude of dyskinesias also increased. Peripheral COMT inhibition with entacapone increased significantly th e bioavailability of levodopa and prolonged its antiparkinsonian effec t after a single dose and after repeated dosing for 4 weeks. Thus enta capone seems to be a valuable adjuvant to levodopa treatment in parkin sonian patients with end-of-dose failure.