title: Development of acetaminophen proline prodrug.
abstract: In this research work, proline ester prodrug of acetaminophen (Pro-APAP) was synthesized and evaluated for its stability in PBS buffer at various pH and Caco-2 cell homogenate. The Pro-APAP is more stable at lower pH than higher pH, with half-life of 120min in PBS buffer at pH 2.0, half-life of 65min at pH 5.0, and half life of 3.5min at pH 7.4, respectively. The half-life of Pro-APAP in Caco-2 cell homogenate is about 1min, much shorter than the half-life in PBS buffer at pH 7.4, indicating enzymes in the cell homogenate contribute to the hydrolysis of the ester bond. Carboxypeptidase A was incubated with Pro-APAP at pH 7.4 with half-life of 3.8min which is very close to the half life in buffer itself. This clearly indicates carboxypeptidase A is not one of the enzymes contributing to the hydrolysis of the prodrug. Physicochemical characteristics such as melting point and stability of newly synthesized prodrug were determined by MDSC technique.
authors.affiliation: Long Island University, Brooklyn, NY 11201, United States. james.wu@liu.edu
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Wu
authors.forename: Ashish
authors.initials: A
authors.lastname: Patel
authors.forename: Rutesh
authors.initials: R
authors.lastname: Dave
authors.forename: Xudong
authors.initials: X
authors.lastname: Yuan
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D018938:Caco-2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D011392:Proline / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D011355:Prodrugs; D000082:Acetaminophen; D011392:Proline