Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects

Eur J Clin Pharmacol. 1996;50(1-2):47-55. doi: 10.1007/s002280050068.


Objective: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects.

Methods: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio 1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone; its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes.

Results: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased Cmax and AUC values. Despite the long halflife of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory Emax model with constant EC50 values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics.

Conclusion: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson's disease.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Benzophenones / adverse effects
  • Benzophenones / pharmacokinetics
  • Benzophenones / pharmacology*
  • Biotransformation
  • Catechol O-Methyltransferase / blood
  • Catechol O-Methyltransferase Inhibitors*
  • Dopamine Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Erythrocytes / drug effects
  • Erythrocytes / enzymology
  • Female
  • Half-Life
  • Humans
  • Levodopa / pharmacology
  • Male
  • Middle Aged
  • Nitrophenols
  • Tolcapone


  • Benzophenones
  • Catechol O-Methyltransferase Inhibitors
  • Dopamine Agents
  • Enzyme Inhibitors
  • Nitrophenols
  • Levodopa
  • Tolcapone
  • Catechol O-Methyltransferase