Investigation into intestinal transport and absorption of an amino acid, amino acid analogue and its peptidomimetic prodrug.
Asgharnejad, Mandana
1992
Abstract
Peptides represent one of the most promising categories of new drugs. Oral delivery of peptides and peptide analogues is a challenging research objective because of the high susceptibility of these compounds to degradation by gastrointestinal digestive enzymes. There have been many attempts, including prodrug approaches, to achieve oral peptide delivery and to explore attending transport mechanisms. One important compound is L-alpha-methyldopa. This compound is an amino acid analogue which is absorbed from the intestine by a concentration-dependent saturable mechanism. In its case, the peptide carrier responsible for transport of a prodrug of L-alpha-methyldopa is less restrictive in its structural requirement and more efficient in its transport of substrate than the amino acid transporter. Potential sites of back conversion of this prodrug can be the intestine and the erythrocyte which are rich in prolidase enzyme. This thesis explores the possibility of using an analogue of L-alpha-methyldopa as a dipeptide prodrug. The specific objectives of the project included: (I) to evaluate alternative strategies in the oral delivery of poorly absorbed amino acids analogues by investigating their dipeptide derivatives as prodrugs, (II) to identify a new in vivo method in examining the intestinal absorption of L-alpha-methyldopa-phenylalanine in the rate model, (III) to characterize the flow characteristics of a new in vivo method, namely chronically isolated intestinal loop (CIIL), (IV) to characterize the oral absorption of the amino acid, L-phenylalanine, and its analogue, L-alpha-methyldopa, in CIIL and to compare the results in this model to the traditional in situ method, and (V) to examine intestinal absorption of the prodrug L-alpha-methyldopa-phenylalanine using the new in vivo method. We have found, using residence time distribution analysis of the fluid elements within the intestine, that "N mixing tanks in series" and "dispersed plug flow" models were appropriate to describe the flow patterns of the CIIL. A time series analysis of output volume measurements in short intervals of time provided additional evidence for better mixing in CIIL than in in situ procedures. Effective permeabilities were obtained and used to characterize the gastrointestinal permeability of absorbed solutes in the CIIL method. In addition, the observed differences in absorption parameters of L-phenylalanine in the ileum and the jejunum indicated a segmental dependence of intestinal absorption. Results indicated the bioavailability of L-alpha-methyldopa in rats following the dose of the prodrug, L-alpha-methyldopa-phenylalanine, was almost three times higher than when an equivalent dose of the drug, L-alpha-methyldopa, was administered alone.Other Identifiers
(UMI)AAI9308267
Subjects
Health Sciences, Pharmacy
Types
Thesis
Metadata
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