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

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, phenylacetyl...

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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
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container_end_page 116
container_issue 2
container_start_page 113
container_title Journal of pharmaceutical sciences
container_volume 81
creator Bai, Jane P.-F.
Hu, Ming
Subramanian, P.
Mosberg, Henry I.
Amidon, Gordon L.
description 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.
doi_str_mv 10.1002/jps.2600810202
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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. 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Pharm. Sci</addtitle><description>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. 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source Wiley Blackwell Single Titles
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
title Utilization of Peptide Carrier System To Improve Intestinal Absorption: Targeting Prolidase as a Prodrug-Converting Enzyme
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