1.Melanoma diagnosed 27 years after a benoxaprofen-induced photosensitivity reaction.
Chin KY1, El-Kayat B, Milne A, Hart A. J Dermatol Case Rep. 2012 Mar 27;6(1):5-7. doi: 10.3315/jdcr.2012.1087.
BACKGROUND: The propionic acid derivative Benoxaprofen was introduced for the treatment of rheumatic disorders in 1980. Its product license was then withdrawn 2 years later due to concerns over serious dermatologic, hepatic and renal side effects. Photosensitivity was the most common side effect with reported incidence of up to 50%.
2.Glucuronidation and covalent protein binding of benoxaprofen and flunoxaprofen in sandwich-cultured rat and human hepatocytes.
Dong JQ1, Smith PC. Drug Metab Dispos. 2009 Dec;37(12):2314-22. doi: 10.1124/dmd.109.028944. Epub 2009 Sep 22.
Benoxaprofen (BNX), a nonsteroidal anti-inflammatory drug (NSAID) that was withdrawn because of hepatotoxicity, is more toxic than its structural analog flunoxaprofen (FLX) in humans and rats. Acyl glucuronides have been hypothesized to be reactive metabolites and may be associated with toxicity. Both time- and concentration-dependent glucuronidation and covalent binding of BNX, FLX, and ibuprofen (IBP) were determined by exposing sandwich-cultured rat hepatocytes to each NSAID. The levels of glucuronide and covalent protein adduct measured in cells followed the order BNX > FLX > IBP. These results indicate that 1) BNX-glucuronide (G) is more reactive than FLX-G, and 2) IBP-G is the least reactive metabolite, which support previous in vivo studies in rats. The proportional increases of protein adduct formation for BNX, FLX, and IBP as acyl glucuronidation increased also support the hypothesis that part of the covalent binding of all three NSAIDs to hepatic proteins is acyl glucuronide-dependent.
3.Effects of clofibric acid on the biliary excretion of benoxaprofen glucuronide and taurine conjugate in rats.
Okada K1, Kanoh H, Mohri K. Pharmazie. 2011 Oct;66(10):777-83.
Benoxaprofen (BOP) is a 2-methyl propionic acid derivative with anti-inflammatory activity. BOP has an asymmetric carbon, and receives chiral inversion from R to S in vivo. BOP is metabolized to glucuronide (BOP-G) and taurine conjugate (BOP-T). The configuration of BOP-G is mainly S, and that of BOP-T is R. Chiral inversion of R to S of the propionic acid moiety and amino acid conjugation of carboxyl compounds proceed via an acyl CoA intermediate. It is known that fibrates, used in hyperlipidemia, induce acyl CoA synthetase and increase CoA concentration. We administered racemic BOP (10 mg/kg body weight) to rats (CFA+) pre-administered clofibric acid (CFA, 280 mg/kg/day), and studied BOP, BOP-G, and BOP-T enantiomer concentrations in plasma and bile up to 12 h after administration. The findings were compared with those in rats (CFA-) that had not received CFA. Furthermore, we studied the amounts of BOP-G enantiomer produced by glucuronidation in vitro using microsomes pretreated with CFA.