INTESTINAL-ABSORPTION OF CAPTOPRIL AND 2 THIOESTER ANALOGS IN RATS AND DOGS

The objectives of this study were (i) to determine whether the reduced absorption of captopril from the colon of humans also occurs in rats and (ii), after confirmation of the relevance of a new rat model, to e valuate the intestinal absorption of captopril and several of its anal ogs. A model was developed and validated in which specific sites withi n the GI tract of rats were surgically implanted with a cannula such t hat animals could be dosed while conscious and unrestrained. The absor ption of captopril after administration into the lower GI tract of rat s was significantly reduced relative to the upper GI tract, which was consistent with results reported previously in humans. In rats, the ab sorption of the S-benzoyl thioester prodrug of captopril (SQ-25868) fr om the lower GI tract was substantially greater than that of captopril . However, the absorption of the S-benzoyl thioester prodrug of 4-phen yl thio-captopril (SQ-26991) from the lower GI tract was only marginal ly better than that of captopril. In additional studies in dogs, a 12h controlled-release formulation of SQ-25868 provided sustained blood l evels of captopril while maintaining acceptable bioavailability (>80%) . Two approaches were tried, without success, to stabilize captopril i n vivo: (i) complexation with zinc (SQ-26284) and (ii) use of ascorbic -acid-buffered (pH 3.5) vehicle. The zinc complex might have failed be cause it has very low solubility, whereas the pH-3.5-buffered vehicle was quickly neutralized within the colonic lumen in rats, and did not stabilize captopril against oxidation. Rapid neutralization might expl ain why the colonic bioavailability of captopril was not substantially increased when this pH-3.5-buffered vehicle was tried in humans.