Effects of Tolcapone, a Catechol-O-Methyltransferase Inhibitor, and Sinemet on Intestinal Electrolyte and Fluid Transport in Conscious Dogs

Abstract

Tolcapone (T) is a novelcatechol-O-methyltransferase (COMT) inhibitor recentlyintroduced for the treatment of Parkinson's disease. Inclinical efficacy studies, T has been associated with alow incidence of diarrhea. The objectives of the study wereto examine whether T and its adjunctive drug Sinemet (S)could influence intestinal fluid and electrolytetransport as a possible cause for the diarrhea. The studies were conducted in conscious dogssurgically prepared with Thiry-Vella loops constructedfrom a 40-cm jejunal segment. A physiologically bufferedtest solution was perfused into the orad stoma and collected from the caudad stoma. Secretionswere collected at 15-min intervals and analyzed forvolume, electrolytes, lipid phosphorus, and protein. Theacute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acuteadministration of S (25 mg/kg) with T (30 mg/kg) wasalso well tolerated. The acute oral administration of Tinduced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, andbicarbonate) secretion (P < 0.05). The oralcoadministration of S (25 mg/kg) with T (30 mg/kg)accelerated the onset of the stimulation of intestinalsecretion. Despite the significant stimulation ofintestinal secretion, none of the dogs developeddiarrhea, indicating the importance of intestinalcompensatory mechanisms. Neither T nor T&S affectedcalcium, lipid, or protein efflux rates, suggesting thatthe stimulated secretion was not a consequence ofintestinal mucosal injury. The chronic (seven-day)administration of T and T&S was associated withreduced intestinal secretory responses when comparedwith the acute administration of the same drugs; Senhanced the T-induced tolerance development. The basisfor such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone onintestinal secretion may, under certain conditions,contribute to the induction of diarrhea in susceptiblepatients.