Tolcapone increases plasma catecholamine levels in patients with Parkinson's disease

Tolcapone is a catechol-ortho-methyl-tranferase (COMT) inhibitor that increases the L-DOPA half-life and the duration of effect in Parkinson's disease. We investigated the effect of tolcapone on the plasma catecholamine levels. We measured plasma catecholamines 2h after the first daily dose of L-DOPA or L-DOPA+tolcapone while resting and 2 and 10min after standing. We also measured the pharmacokinetics of L-DOPA and 3-OM-DOPA and the clinical response to the medication for 6h after the early morning dose. The levels of dopamine, norepinephrine, adrenaline and total catecholamines significantly increased and 3-OM-DOPA decreased with tolcapone. We did not observe significant changes in the plasma L-DOPA levels at the doses of tolcapone used in this study. Tolcapone side effects included worsening of dyskinesia and psychosis, diarrhea and elevation of liver enzymes. Twenty-four-hour ambulatory recording of arterial blood pressure and heart rate did not reveal cardiovascular side effects in patients treated with tolcapone for less than 1year. Since adrenergic stimulation may increase the hepatotoxic potential of commonly used drugs, usually thought of as safe for the liver, we postulate that some of the already reported life threatening complications of tolcapone could be related to excessive adrenergic stimulation by high catecholamine levels caused by inhibition of COMT activity.