Benoxaprofen

Benoxaprofen (LRCL 3794) is a nonsteroidal anti-inflammatory agent that blocks the biosynthesis of inflammatory mediators such as leukotrienes and prostaglandins by inhibiting 5-LOX, PGH2 synthase and cytochrome P-450. Benoxaprofen exhibits significant toxicity: it not only alters cellular redox status, uncouples oxidative phosphorylation and disrupts calcium ion homeostasis, but also causes liver injury through the formation of covalent adducts between its active metabolites and hepatic proteins. Benoxaprofen shows strong phototoxicity under ultraviolet irradiation, and induces erythrocyte lysis, mast cell degranulation and histamine release. Benoxaprofen is widely used in studies of urticaria and related phototoxic mechanisms^[1][2][3][4].
In Vitro:Benoxaprofen (0.25-2.5 mM; 10-15 min) binds to cytochrome P-450 in rat liver microsomes to form a type I spectral complex, and competitively inhibits aminopyrine demethylation with a K_i value of 0.38 mM^[1].
Benoxaprofen (0.75-1.25 mM; 2-4 h) does not alter the increased L/P ratio or ALT release it induces in uninduced isolated rat hepatocytes^[1].
Benoxaprofen inhibits the production of iSRS, i12-HETE and PGE₂ stimulated by A-23187 in RBL-1 cells, with IC₅₀ values of 0.4 μM, 0.45 μM, and 1.3 μM, respectively^[2].
Benoxaprofen (50 μg/mL; 24 h) does not form detectable irreversible adducts with human serum albumin at pH 7.4 and 37 °C^[3].
Benoxaprofen (8 μM; 10 min, irradiated) induces photolysis of human erythrocytes; hemolysis occurs faster and earlier under aerobic conditions compared with anaerobic conditions, whereas no hemolysis takes place in dark environments^[4]. In Vivo:Benoxaprofen (20 mg/kg; i.v.; single bolus dose) administered intravenously to male Sprague-Dawley rats results in detectable plasma protein adducts over 8 h, with a systemic BNX-G AUC_0→8h of 1.98 ± 0.59 μg h/mL and hepatobiliary BNX-G excretion of 10.8 ± 1.4% of the dose, while liver protein adducts remain undetectable^[3].
Benoxaprofen (20-200 mg/kg; i.p.; single dose) administered intraperitoneally to male Sprague-Dawley rats results in dose-proportional liver protein adduct formation and dose-dependent covalent modification of ~70 kDa and ~110 kDa hepatic proteins at 8 h post-administration^[3].
Benoxaprofen (100 mg/kg; i.p.; single dose) administered intraperitoneally to male Sprague-Dawley rats results in time-dependent covalent modification of ~70 kDa and ~110 kDa hepatic proteins detectable from 4 to 24 h post-administration^[3].