Optimizing levodopa pharmacokinetics with multiple tolcapone doses in the elderly

Clin Pharmacol Ther. 1997 Sep;62(3):300-10. doi: 10.1016/S0009-9236(97)90033-3.


Objectives: The multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, were assessed in healthy elderly volunteers receiving concomitant carbidopa and levodopa.

Methods: Thirty-six volunteers from 55 to 75 years old participated in this double-blind, placebo-controlled, ascending multiple-dose study. Tolcapone was studied at dosages of 100, 200, 400, or 800 mg three times daily (t.i.d.) in four sequential groups. Each group consisted of nine participants who had been randomized to receive either placebo (n = 3) or tolcapone (n = 6). Tolcapone or placebo was coadministered with carbidopa and levodopa (25 and 100 mg, respectively) for 7 days. Assessments included tolerability, pharmacokinetics of tolcapone, levodopa, and 3-O-methyldopa, and inhibition of COMT activity in erythrocytes.

Results: By inhibiting COMT, tolcapone reduced levodopa metabolism to 3-O-methyldopa, resulting in a twofold increase in levodopa exposure (area under the curve) and elimination half-life, without changing levodopa peak plasma concentration. These effects were similar on days 1 and 7 of treatment. Development of tolerance to COMT inhibition was not observed. Onset of effect was rapid (day 1 of treatment), and the maximum effect on levodopa pharmacokinetics was already observed with 100 or 200 mg tolcapone t.i.d. At these dosages, tolcapone pharmacokinetics were linear and stable; accumulation occurred with 800 mg t.i.d. The combination of tolcapone and carbidopa-levodopa was generally well tolerated, although more nausea and vomiting were observed at higher dosages (400 to 800 mg t.i.d.), particularly in women.

Conclusion: Tolcapone shows promise as an effective adjunct to levodopa in the treatment of Parkinson's disease. Clinical pharmacology data indicate that the therapeutic regimen should be 100 or 200 mg t.i.d.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aged
  • Analysis of Variance
  • Antiparkinson Agents / adverse effects
  • Antiparkinson Agents / pharmacokinetics
  • Antiparkinson Agents / pharmacology*
  • Benzophenones / adverse effects
  • Benzophenones / pharmacokinetics
  • Benzophenones / pharmacology*
  • Catechol O-Methyltransferase Inhibitors*
  • Dopamine Agents / administration & dosage
  • Dopamine Agents / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Interactions
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Erythrocytes / drug effects
  • Erythrocytes / enzymology
  • Female
  • Gastrointestinal Diseases / chemically induced
  • Humans
  • Levodopa / administration & dosage
  • Levodopa / pharmacokinetics*
  • Male
  • Middle Aged
  • Nervous System Diseases / chemically induced
  • Nitrophenols
  • Tolcapone


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