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pGlu-L-Dopa-Pro: A Tripeptide Prodrug Targeting the Intestinal Peptide Transporter for Absorption and Tissue Enzymes for Conversion

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Abstract

Purpose. The purpose of this study is to investigate the characteristics of pGlu-L-Dopa-Pro as a prodrug of L-Dopa.

Methods. pGlu-L-Dopa-Pro and L-Dopa-Pro were synthesized using the standard procedures of peptide synthesis. The conversion of pGlu-L-Dopa-Pro to L-Dopa was studied using pyroglutamyl aminopeptidase I and prolidase. With rats as the animal model, the stability of pGlu-L-Dopa-Pro in intestinal homogenates was determined, then the transport characteristics of pGlu-L-Dopa-Pro were studied using in-situ perfusion and Ussing chambers.

Results. pGlu-L-Dopa-Pro, relatively stable in intestinal homogenates and intestinal fluid, had a dimensionless permeability of 1.8 at 0.04 mM. Its intestinal permeability was significantly inhibited by 20 mM captopril, by a mixture of dipeptides, 80 mM Gly-Gly and 5 mM Gly-Pro, and by 2 mM cephradine. Further, in Ussing chambers, its mucosal to serosal permeability decreased dramatically with concentration. Conversion studies showed that pGlu-L-Dopa-Pro was degraded by pyroglutamyl aminopeptidase I, an enzyme releasing the N-terminal pyroglutamic acid, with Vmax and Km of 0.6 µmole/min/g protein and 21 mM, respectively, and that L-Dopa-Pro was degraded by prolidase with Vmax and Km of 44 µmole/min/g protein and 0.48 mM, respectively.

Conclusions. This tripeptide, a potential prodrug of L-Dopa, is absorbed by the intestinal peptide transporter, is relatively stable in the gut wall, and is converted to L-Dopa by peptidases with the cleavage by pyroglutamyl aminopeptidase I to L-Dopa-Pro as the rate limiting step.

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  1. Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, 55455

    Jane P. F. Bai

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Bai, J.P.F. pGlu-L-Dopa-Pro: A Tripeptide Prodrug Targeting the Intestinal Peptide Transporter for Absorption and Tissue Enzymes for Conversion. Pharm Res 12, 1101–1104 (1995). https://doi.org/10.1023/A:1016239321494

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  • DOI: https://doi.org/10.1023/A:1016239321494

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