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) inhibitor, 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 administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before 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 clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.
Department of Neurosciences, Clinical Neurology, University of Pisa, Italy.
A
A
Napolitano
P
P
Del Dotto
L
L
Petrozzi
G
G
Dell'Agnello
G
G
Bellini
G
G
Gambaccini
U
U
Bonuccelli
D000978:Antiparkinson Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D009596:Nitrophenols; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D000077867:Tolcapone; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics
D000978:Antiparkinson Agents; D001577:Benzophenones; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D014443:Tyrosine; D007980:Levodopa; D000077867:Tolcapone; C008404:3-methoxytyrosine