title: Enzymologic and pharmacologic profile of loxoprofen sodium and its metabolites.
abstract: We investigated the mechanism of inhibition of loxoprofen sodium, a non-steroidal anti-inflammatory drug (NSAID), and its active metabolite (loxoprofen-SRS) on cyclooxygenase (COX). In in vitro assays, loxoprofen sodium appeared inactive against recombinant human COX-1 and COX-2, whereas loxoprofen-SRS inhibited both. In the investigation of kinetic behavior, loxoprofen-SRS showed time-dependent inhibition for both isozymes. Human whole blood assay also showed that loxoprofen-SRS possesses the profile of a non-selective inhibitor for COX. In a rat air pouch model, oral administration of loxoprofen sodium lowered prostaglandin (PG) E2 in both fluid exudates of the inflammatory pouch and stomach tissue with ED50 values of 2.0 and 2.1 mg/kg, respectively. Additionally, platelet thromboxane B2 production was also inhibited by loxoprofen sodium (ED50 of 0.34 mg/kg). In a rat carrageenan-induced paw edema model, loxoprofen sodium dose-dependently reduced the paw edema, accompanied by a decrease in PGE2 content in inflamed paw exudates. These findings suggest that the COX inhibitory activity of loxoprofen sodium is attributable to its active metabolite, loxoprofen-SRS, and that loxoprofen-SRS shows non-selective inhibition for COX.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc, Japan. masahiro.noguchi@jp.astellas.com
authors.forename: Masahiro
authors.initials: M
authors.lastname: Noguchi
authors.forename: Aishi
authors.initials: A
authors.lastname: Kimoto
authors.forename: James Kevin
authors.initials: JK
authors.lastname: Gierse
authors.forename: Mark Crossfield
authors.initials: MC
authors.lastname: Walker
authors.forename: Ben Scott
authors.initials: BS
authors.lastname: Zweifel
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Nozaki
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D005528:Foot / Q000473:pathology; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D010544:Peroxidases / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010666:Phenylpropionates; C040656:loxoprofen; D013929:Thromboxane B2; D010544:Peroxidases; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone