title: Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans.
abstract: OBJECTIVE
  To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers.
  
  
  METHODS
  In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes.
  
  
  RESULTS
  Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity.
  
  
  CONCLUSIONS
  The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
authors.forename: K M
authors.initials: KM
authors.lastname: Jorga
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
authors.forename: R
authors.initials: R
authors.lastname: Gieschke
authors.forename: B
authors.initials: B
authors.lastname: Fotteler
authors.forename: G
authors.initials: G
authors.lastname: Zürcher
authors.forename: M
authors.initials: M
authors.lastname: Da Prada
authors.forename: P
authors.initials: P
authors.lastname: van Brummelen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001577:Benzophenones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D009596:Nitrophenols; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone