Utilization of peptide carrier system to improve intestinal absorption: targeting prolidase as a prodrug-converting enzyme.
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.
Bai
J P
JP
College of Pharmacy, University of Minnesota, Minneapolis 55455.
Hu
M
M
Subramanian
P
P
Mosberg
H I
HI
Amidon
G L
GL
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
D004337:Drug Carriers; D010455:Peptides; D011355:Prodrugs; D004150:Dipeptidases; C022449:proline dipeptidase