title: Carboxyl nonsteroidal anti-inflammatory drugs are efficiently glucuronidated by microsomes of the human gastrointestinal tract.
abstract: Limited studies have been carried out on the biotransformation of carboxyl nonsteroidal anti-inflammatory drugs (NSAIDs) in the liver. However, the role of the intestine in NSAID metabolism has not been investigated. In this report, the contribution of UDP-glucuronosyltransferases (UGTs) in the human gastrointestinal (GI) tract from five donors to the glucuronidation of the NSAIDs, RS-ketoprofen, S-naproxen, RS- and S-etodolac, was investigated. UGT activity and, for some donors, mRNA levels were evaluated. All NSAIDs were glucuronidated throughout the GI tract; however, glucuronidation was low in stomach and duodenum as compared to the remainder of the intestine. RT-PCR analysis demonstrated that the UGT1A isoforms, UGT1A3, 1A8, and 1A10, and UGT2B7 were expressed in the GI tract. Human recombinant UGT1A3, 1A9, 1A10 and 2B7 were actively involved in the glucuronidation of all NSAIDs while UGT1A7 and the intestine-specific UGT1A8 had no glucuronidating activity towards those compounds. Despite interindividual variations in both the levels of mRNA and the distribution of activity through the intestine, UGTs in the GI tract may contribute significantly to the first pass metabolism of orally administered NSAIDs.
authors.affiliation: UMR 7561 CNRS-Université Henri Poincaré, Nancy I, Faculté de Médecine, BP 184, F 54505 Vandoeuvre-lès-Nancy Cedex, France. Nicole.Sabolovic@medecine.uhp-nancy.fr
authors.forename: Nicole
authors.initials: N
authors.lastname: Sabolovic
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Heydel
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Little
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Humbert
authors.forename: Anna
authors.initials: A
authors.lastname: Radominska-Pandya
authors.forename: Jacques
authors.initials: J
authors.lastname: Magdalou
mesh_terms: D000284:Administration, Oral; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D017308:Etodolac / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007660:Ketoprofen / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism*; D009288:Naproxen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020719:Glucuronides; D012333:RNA, Messenger; D017308:Etodolac; D009288:Naproxen; D007660:Ketoprofen; D014453:Glucuronosyltransferase