Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease. In clinical efficacy studies, T has been associated with a low incidence of diarrhea. The objectives of the study were to examine whether T and its adjunctive drug Sinemet (S) could influence intestinal fluid and electrolyte transport as a possible cause for the diarrhea. The studies were conducted in conscious dogs surgically prepared with Thiry-Vella loops constructed from a 40-cm jejunal segment. A physiologically buffered test solution was perfused into the orad stoma and collected from the caudad stoma. Secretions were collected at 15-min intervals and analyzed for volume, electrolytes, lipid phosphorus, and protein. The acute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acute administration of S (25 mg/kg) with T (30 mg/kg) was also well tolerated. The acute oral administration of T induced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, and bicarbonate) secretion (P < 0.05). The oral coadministration of S (25 mg/kg) with T (30 mg/kg) accelerated the onset of the stimulation of intestinal secretion. Despite the significant stimulation of intestinal secretion, none of the dogs developed diarrhea, indicating the importance of intestinal compensatory mechanisms. Neither T nor T&S affected calcium, lipid, or protein efflux rates, suggesting that the stimulated secretion was not a consequence of intestinal mucosal injury. The chronic (seven-day) administration of T and T&S was associated with reduced intestinal secretory responses when compared with the acute administration of the same drugs; S enhanced the T-induced tolerance development. The basis for such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone on intestinal secretion may, under certain conditions, contribute to the induction of diarrhea in susceptible patients.