EFFECTS OF TOLCAPONE, A CATECHOL-O-METHYLTRANSFERASE INHIBITOR, AND SINEMET ON INTESTINAL ELECTROLYTE AND FLUID TRANSPORT IN CONSCIOUS DOGS

Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease. In clin ical efficacy studies, T has been associated with a low incidence of d iarrhea. The objectives of the study were to examine whether T and its adjunctive drug Sinemet (S) could influence intestinal fluid and elec trolyte transport as a possible cause for the diarrhea. The studies we re conducted in conscious dogs surgically prepared with Thiry-Vella lo ops constructed from a 40-cm jejunal segment. A physiologically buffer ed test solution was perfused into the orad stoma and collected from t he caudad stoma. Secretions were collected at 15-min intervals and ana lyzed for volume, electrolytes, lipid phosphorus, and protein. The acu te oral administration of T (10 and 30 mg/kg doses) was well tolerated . Concurrent acute administration of S (25 mgikg) with T (30 mg/kg) wa s also well tolerated. The acute oral administration of T induced a do se-dependent efflux of intestinal fluid and electrolytes (sodium, pota ssium, chloride, and bicarbonate) secretion (P < 0.05). The oral coadm inistration of S (25 mg/kg) with T (30 mgikg) accelerated the onset of the stimulation of intestinal secretion. Despite the significant stim ulation of intestinal secretion, none of the dogs developed diarrhea, indicating the importance of intestinal compensatory mechanisms. Neith er T nor T&S affected calcium, lipid, or protein efflux rates, suggest ing that the stimulated secretion was not a consequence of intestinal mucosal injury. The chronic (seven-day) administration of T and T&S wa s associated with reduced intestinal secretory responses when compared with the acute administration of the same drugs S enhanced the T-indu ced tolerance development. The basis for such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone on intestin al secretion may, under certain conditions, contribute to the inductio n of diarrhea in susceptible patients.