Investigation into drug and drug analogs transported by the peptide carrier system: Intestinal absorption of captopril and of peptidyl derivatives of methyldopa.

Abstract

Oral delivery of peptides and peptide analogs is a very challenging task since these compounds are highly suseptible to various digestive enzymes. Formation of common guidelines for successful oral delivery is extremely critical. The projects is focused on some important areas which will contribute to these guidelines, i.e., (a) to define an appropriate experimental approach, (b) to underst and the basic principles of peptide transport in small intestine, and (c) to apply these principles to the study of drugs which is peptides or peptide analogs. Furthermore, a dipeptidase, prolidase, was also studied to see how the enzyme may affect the metabolism of selected dipeptides and to test if the enzyme could be targeted as a prodrug converting enzyme. A single-pass perfusion in rat jejunum in situ was used as the experimental method for transport study while established enzymatic procedures were followed to study prolidase. A boundary analysis model which separates the aqueous resistance from the overall resistance, was verified experimentally by model compounds (amino acids and dipeptides). It was applied to the study of the absorption mechanism of drug and drug analogs transported by carrier-mediated process. Results of perfusion studies of "designer" dipeptidyl derivatives of L-$\\alpha$-methyldopa (mdopa) showed that the permeabilities of these derivatives were significantly improved compared to mdopa. Moreover, high permeabilities of $\\alpha$-alkyl substituted amino acid-containing peptides indicate that this group of peptides is well transported by small intestine. In addition, systemic studies were designed to investigate the absorption mechanism of captopril. Results demonstrated that the absorption of captopril was pH and concentration dependent. The absorption is mainly via peptide carrier system (by inhibition studies). Prolidase is a specific cytosolic enzyme. Captopril inhibited its activity. The results of captopril hydrolysis studies showed that captopril was a poor substrate but a potent inhibitor. Moreover, the hydrolysis is a new metabolic pathway for the captopril biotransformation. L-$\\alpha$-Methyldopa-L-proline which has a C-terminal proline, was also tested as a substrate. Subsequent studies have shown that L-$\\alpha$-Methyldopa-L-proline has good affinity for the carrier but has a relatively small maximum velocity.