title: Chemical reactivity of the naproxen acyl glucuronide and the naproxen coenzyme A thioester towards bionucleophiles.
abstract: Drugs may be metabolised to reactive electrophilic species that spontaneously react with proteins. The presence of such drug-protein adducts has been associated with drug toxicity. In this study, the reactivity of the major metabolite of naproxen--the 1-beta-O-glucuronide (Nap-GlcU)--was compared to the corresponding naproxen coenzyme A (Nap-CoA) thioester. The reactivity of the two metabolites was assessed in vitro in a phosphate buffer (pH 7.4; 0.1 M) at 37 degrees C towards the model bionucleophiles glutathione and human serum albumin (HSA). The reaction between the electrophilic species (Nap-GlcU and Nap-CoA) and glutathione forming the Nap-glutathione conjugate was monitored using LC-MS-MS and LC-UV, respectively. It was shown that Nap-CoA resulted in an approximate 100-fold higher formation of Nap-glutathione conjugate than Nap-GlcU. The presence of Nap-CoA also resulted in acylated HSA with a rate and a yield that was significantly higher than reported for Nap-GlcU. In summary, the data suggest that CoA metabolites may be more reactive species than acyl glucuronides that previously have been associated with severe drug related side effects in vivo.
authors.affiliation: Department of Analytical and Pharmaceutical Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark. jol@dfh.dk
authors.forename: Jørgen
authors.initials: J
authors.lastname: Olsen
authors.forename: Inga
authors.initials: I
authors.lastname: Bjørnsdottir
authors.forename: Jette
authors.initials: J
authors.lastname: Tjørnelund
authors.forename: Steen
authors.initials: S
authors.lastname: Honoré Hansen
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003065:Coenzyme A / Q000737:chemistry / Q000378:metabolism*; D004347:Drug Interactions; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009288:Naproxen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020719:Glucuronides; C430408:naproxen glucuronide; D009288:Naproxen; D005978:Glutathione; D003065:Coenzyme A