title: Pharmacokinetics, pharmacodynamics, and tolerability of tolcapone: a review of early studies in volunteers.
abstract: Tolcapone is a potent, reversible inhibitor of catechol O-methyltransferase (COMT) intended for use as an adjunct to levodopa therapy for Parkinson's disease (PD). Findings from the first pharmacokinetics/pharmacodynamics and tolerability studies of tolcapone in volunteers are reviewed. Following linear and dose-proportional pharmacokinetics, tolcapone is rapidly absorbed and eliminated after single- or multiple-dose (i.e., tid) administration. Onset of COMT inhibition is rapid, substantial, and reversible, and is not affected by the co-administration of levodopa/decarboxylase inhibitor (levodopa/DCI). When given together with levodopa/DCI, tolcapone increases the relative bioavailability and plasma elimination half-life of levodopa, without affecting its peak plasma concentration. This leads to more stable plasma levels of levodopa, and the formation of 3-O-methyldopa is effectively reduced. Tolcapone was well tolerated alone or in combination with levodopa/DCI, and the results indicated that the effective dose in patients with PD would be in the range of 50-400 mg tid.
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche, Ltd., Basel, Switzerland.
authors.forename: K M
authors.initials: KM
authors.lastname: Jorga
mesh_terms: D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001577:Benzophenones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D065098:Catechol O-Methyltransferase Inhibitors; D002986:Clinical Trials as Topic; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007980:Levodopa / Q000493:pharmacokinetics*; D009596:Nitrophenols; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology; D000077867:Tolcapone; D014838:Volunteers
chemical_list: D000978:Antiparkinson Agents; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D007980:Levodopa; D000077867:Tolcapone