title: Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver.
abstract: 1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 microg NAP equivalents ml perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t 1/2) of 13.4 +/- 4.4h. No metabolites were detected in perfusate, while NAG was the only metablolite present in bile in measurable amounts (3.9 +/- 0.8% of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t 1/2 in perfusate = 57 +/- 3 and 75 +/- 14 min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.
authors.affiliation: Centre for Studies in Drug Disposition, The University of Queensland, Royal Brisbane Hospital, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Lo
authors.forename: R S
authors.initials: RS
authors.lastname: Addison
authors.forename: W D
authors.initials: WD
authors.lastname: Hooper
authors.forename: R G
authors.initials: RG
authors.lastname: Dickinson
mesh_terms: D000215:Acylation; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D006207:Half-Life; D006868:Hydrolysis; D007536:Isomerism; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009288:Naproxen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020719:Glucuronides; D009288:Naproxen