S1302 Dose-Related Effects of Chenodeoxycholate on Gastrointestinal and Colonic Transit and Bowel Function in Female Patients With Constipation-Predominant Irritable Bowel Syndrome

Abstract

Background: A3309 modulates the enterohepatic circulation of bile acids (BA) by inhibiting the intestinal bile acid transporter (IBAT). This will result in an increased concentration of BA in the colon. The synthesis of bile acids in the liver can be measured indirectly by plasma concentrations of the intermediate 7-α-hydroxy-4-cholesten-3-one (C4). Methods: In Vitro part: A3309 potency was tested in transfected HEK293 cells. The cells expressing the various BA transporters were grown in Cytostar 96 w Scintillation Proximity Assay plates and the effect of increasing concentrations of A3309 on accumulation of 30 μM of radiolabelled glycocholic acid was monitored. In Vivo part: In dogs, constipation was induced by shifting the standard diet to ground beef dosed once daily until the faeces weight was <30 g/day. Vehicle or test compounds (A3309 or the active comparator tegaserod) were administered once daily for 3 days, and faeces was collected and weighed on a daily basis. The pharmacodynamic effect of A3309 was investigated in a 1-month study in 24 dogs by measuring the plasma concentration of C4. Results: A3309 was found to be highly potent and selective for IBAT with IC50 =0.53±0.17, 0.13±0.03 and 5.8±1.6 nM for the human, mouse and canine transporters, respectively, whereas the corresponding value for the human liver (basolateral) sodium/bile acid co-transporter was found to be 0.24±0.02 μM (400-fold higher than for IBAT inhibition). Furthermore, inhibition of amino acid uptake via the neutral amino acid transporter(s) in the HEK293 cells was at least 1000 times lower than that of BA transport via the human ileal bile acid transporter. In the constipated dog, A3309 increased faeces weight from 9.4+12.4 g/day (mean±SEM n=36) after vehicle to 25.8 g/day (1.5 μmol/kg, n=2), 34.4 g/day (5 μmol/kg, n=2), 31.3±4,5 g/day (15 μmol/kg, n=6) and for tegaserod 14 g/day (3.3 μmol/kg, n=1), 18.1±10,2g/day (3.3 μmol /kgx2, n=3), 23.9±7,1 g/day (10 μmol /kg, n=3) and 68.3 g/day (33 μmol /kgx2, n=2). In the dog, a dose dependant increase of C4 in plasma was observed already after single doses. After 26 days treatment with A3309 the plasma concentration of C4 increased 3 to 7 fold (43.0±8.43,150±48.8 ,190±47.0 and 350±49.0 nmol/L, pre-values, 5, 25, 200 μmol/kg, respectivly). Conclusion: A3309 was found to be highly potent and selective for IBAT and ameliorate meat-induced constipation in dogs. The increased BA synthesis effect last for at least 1 month. IBAT inhibitors have a potential clinical utility in the treatment of constipation.