title: Utilization of peptide carrier system to improve intestinal absorption: targeting prolidase as a prodrug-converting enzyme.
abstract: The feasibility of targeting prolidase as a peptide prodrug-converting enzyme has been examined. The enzymatic hydrolysis by prolidase of substrates for the peptide transporter L-alpha-methyldopa-pro and several dipeptide analogues without an N-terminal alpha-amino group (phenylpropionylproline, phenylacetylproline, N-benzoylproline, and N-acetylproline) was investigated. The Michaelis-Menten parameters Km and Vmax for L-alpha-methyldopa-pro are 0.09 +/- 0.02 mM and 3.98 +/- 0.25 mumol/min/mg protein, respectively. However, no hydrolysis of the dipeptide analogues without an N-terminal alpha-amino group is observed, suggesting that an N-terminal alpha-amino group is required for prolidase activity. These results demonstrate that prolidase may serve as a prodrug-converting enzyme for the dipeptide-type prodrugs, utilizing the peptide carrier for transport of prodrugs into the mucosal cells and prolidase, a cytosolic enzyme, to release the drug. However, a free alpha-amino group appears to be necessary for prolidase hydrolysis.
authors.affiliation: College of Pharmacy, University of Minnesota, Minneapolis 55455.
authors.forename: J P
authors.initials: JP
authors.lastname: Bai
authors.forename: M
authors.initials: M
authors.lastname: Hu
authors.forename: P
authors.initials: P
authors.lastname: Subramanian
authors.forename: H I
authors.initials: HI
authors.lastname: Mosberg
authors.forename: G L
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004150:Dipeptidases / Q000378:metabolism*; D004337:Drug Carriers; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats
chemical_list: D004337:Drug Carriers; D010455:Peptides; D011355:Prodrugs; D004150:Dipeptidases; C022449:proline dipeptidase