Utilization of Peptide Carrier System To Improve Intestinal Absorption: Targeting Prolidase as a Prodrug-Converting Enzyme

• Published in: Journal of pharmaceutical sciences 1992-02, Vol.81 (2), p.113-116
• Main Authors: Bai, Jane P.-F., Hu, Ming, Subramanian, P., Mosberg, Henry I., Amidon, Gordon L.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Chromatography, High Pressure Liquid; Dipeptidases - metabolism; Drug Carriers; General pharmacology; In Vitro Techniques; Intestinal Absorption - physiology; Life Sciences (General); Medical sciences; Peptides - metabolism; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Prodrugs - metabolism; Rats; Space life sciences
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600810202

The feasibility of targeting prolidase as a peptide prodrugconverting enzyme has been examined. The enzymatic hydrolysis by prolidase of substrates for the peptide transporter L-α-methyldopa-pro and several dipeptide analogues without an N-terminal α-amino group (phenylpropionyiproline, phenylacetylproline, N-benzoylproline, and N-acetylproline) was investigated. The Michaelis-Menten parameters Kmand Vmax for L-α-methyldopa-pro are 0.09 ± 0.02mM and 3.98 ± 0.25 µmol/min/mg protein, respectively. However, no hydrolysis of the dipeptide analogues without an N-terminal α-amino group is observed, suggesting that an N-terminal α-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 α-amino group appears to be necessary for prolidase hydrolysis.