Pharmacokinetics and pharmacodynamics of L-DOPA after acute and 6-week tolcapone administration in patients with Parkinson's disease

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inh ibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administrati on on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease ( PD) patients with predictable motor fluctuations. Tapping test, walking rim e, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed bef ore and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This c linical and pharmacokinetic study was repeated after 6 weeks of tolcapone t herapy (200 mg three times daily). It was observed that tolcapone, after bo th acute and chronic administration, prolonged the motor improvement induce d by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours s pent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimin ation of L-Dopa from plasma, whereas the maximal concentration of L-Dopa wa s not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approxima tely one sixth of pre-tolcapone values. The data confirm that tolcapone dec reases L-Dopa clearance and prolongs motor response in PD patients with mot or fluctuations, and that this effect is maintained after 6 weeks of tolcap one therapy.