DISTRIBUTION OF THE DIPEPTIDE TRANSPORTER SYSTEM ALONG THE GASTROINTESTINAL-TRACT OF RATS BASED ON ABSORPTION OF A STABLE AND SPECIFIC PROBE, SQ-29852

Peptidic drugs such as beta-lactam aminocephalosporin antibiotics (e.g ., cephalexin) and the ACE inhibitors lisinopril, quinapril, and benza zepril are apparently absorbed, at least in part, by the intestinal di peptide transporter system (DTS). Although many properties of the DTS have been elucidated, including isolation of the carrier protein, litt le is known about the distribution of this transporter along the gastr ointestinal (GI) tract. The objectives of the present study were to (1 ) validate that SQ-29852 (a lysylproline ACE inhibitor) is a stable an d specific probe for evaluation of the DTS in rats and (2) provide fun damental in vivo information on the distribution of the DTS along the GI tract of rats. Most of the previous studies that explored the locat ion of the DTS typically involved either in vitro uptake or in situ di sappearance of unstable or nonspecific probes. SQ-29852, on the other hand, is an ideal probe for evaluation of the DTS because it is chemic ally and metabolically stable and it is absorbed almost exclusively by the DTS. SQ-29852 appears to be a specific probe for the DTS because the dose-dependent reduction in absorption from about 60% to less than 8% (3 and 3000 mg/kg, respectively) suggests that at least 85% of an orally administered low dose of SQ-29852 is absorbed by a saturable pr ocess, which was shown previously to be the DTS. [C-14]SQ-29852 was ad ministered by gavage to intact rats and via an indwelling cannula in o ne of the following sections of the intestine: duodenum, jejunum, ileu m and proximal colon (n = 4 for each site). On the basis of the recove ry of [C-14]SQ-29852 in urine, the DTS is apparently distributed throu ghout the entire GI tract of rats, including the proximal colon. The p resent results are consistent with previously reported results on the absorption of natural dipeptides in humans and rats and immunohistoche mical evaluation in rats; however, they disagree with a recent report in humans with amoxicillin. This difference is discussed in terms of t he specificity and stability of various drugs that have been used as p robes of the DTS.