title: Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9.
abstract: 1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4'-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9). 2. Although the K(m) and CL(int) values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in Vmax values (liver microsomes, humans > monkeys; intestinal microsomes, humans < monkeys) were observed, no significant differences were noted in the K(m) or S50, Vmax and CL(int) or CLmax values for the 4'-glucuronidation of liver and intestinal microsomes between humans and monkeys. 3. The activities of 6-glucuronidation in recombinant UGT enzymes were UGT1A1 > UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4'-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys. 4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys.
authors.affiliation: a Faculty of Pharmaceutical Sciences , Okayama University , Okayama , Japan .
authors.forename: Naoki
authors.initials: N
authors.lastname: Kishi
authors.affiliation: a Faculty of Pharmaceutical Sciences , Okayama University , Okayama , Japan .
authors.forename: Akane
authors.initials: A
authors.lastname: Takasuka
authors.affiliation: a Faculty of Pharmaceutical Sciences , Okayama University , Okayama , Japan .
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kokawa
authors.affiliation: b Department of Biochemical Toxicology , and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Isobe
authors.affiliation: c Department of Clinical Pharmacy , Yokohama University of Pharmacy , Yokohama , Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Taguchi
authors.affiliation: c Department of Clinical Pharmacy , Yokohama University of Pharmacy , Yokohama , Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Shigeyama
authors.affiliation: c Department of Clinical Pharmacy , Yokohama University of Pharmacy , Yokohama , Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Murata
authors.affiliation: a Faculty of Pharmaceutical Sciences , Okayama University , Okayama , Japan .
authors.forename: Manabu
authors.initials: M
authors.lastname: Suno
authors.affiliation: b Department of Biochemical Toxicology , and.
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Hanioka
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism*; D000090264:UDP-Glucuronosyltransferase 1A9; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D020719:Glucuronides; D014453:Glucuronosyltransferase; D020849:Raloxifene Hydrochloride; D011994:Recombinant Proteins; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C454320:UDP-glucuronosyltransferase, UGT1A8
keywords: Glucuronidation; humans; intestinal microsomes; liver microsomes; monkeys; raloxifene