Enzymologic and pharmacologic profile of loxoprofen sodium and its metabolites.
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.
Noguchi
Masahiro
M
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc, Japan. masahiro.noguchi@jp.astellas.com
Kimoto
Aishi
A
Gierse
James Kevin
JK
Walker
Mark Crossfield
MC
Zweifel
Ben Scott
BS
Nozaki
Kazutoshi
K
Sasamata
Masao
M
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
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