title: Chemical and in vitro enzymatic stability of newly synthesized celecoxib lipophilic and hydrophilic amides.
abstract: Five celecoxib (CXB) acylamide sodium salts, MP-CXB, Cy-CXB, Bz-CXB, CBz-CXB and FBz-CXB were synthesized and characterized. Two simple, fast and validated RP-HPLC methods were developed for simultaneous quantitative determination of the amides and celecoxib in aqueous and biological samples and LOD and LOQ were ≤13.6 and ≤40ng/mL, respectively. The solubility and logP(app) of the amides, in relevant media, were determined. The chemical hydrolysis, at 60, 70 and 80°C, of MP-CXB was studied at GIT-relevant pH (1.2, 6.8 and 7.4) and of CY-CXB was studied at skin relative pH (5.4 and 7.4). Significant hydrolysis was observed for MP-CXB at pH 1.2 only with half-lives 28.28, 11.64 and 3.53h at 60, 70 and 80°C, respectively, with extrapolated half-lives of 2060 and 443h at 25 and 37°C, respectively. The hydrolysis of all amides was studied in rat live homogenate and only Cy-CXB was hydrolyzed with half-life of 3.79h. The hydrolysis of MP-CXB and Cy-CXB was studied in human plasma and neither was hydrolyzed. It is finally suggested that hydrophobic interactions plays a role in the binding of susceptible acylamides to the hepatic hydrolyzing enzyme since only amides with saturated hydrocarbon chains underwent hydrolysis.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Jordan University of Science and Technology, Irbid, Jordan. drqandil@just.edu.jo
authors.forename: Amjad M
authors.initials: AM
authors.lastname: Qandil
authors.forename: Farah H
authors.initials: FH
authors.lastname: El Mohtadi
authors.forename: Bassam M
authors.initials: BM
authors.lastname: Tashtoush
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D000068579:Celecoxib; D015195:Drug Design; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008099:Liver / Q000378:metabolism; D015394:Molecular Structure; D010949:Plasma / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D000577:Amides; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib