Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9

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 intesti...

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Bibliographic Details
Published in:Xenobiotica 2016-04, Vol.46 (4), p.289-295
Main Authors: Kishi, Naoki, Takasuka, Akane, Kokawa, Yuki, Isobe, Takashi, Taguchi, Maho, Shigeyama, Masato, Murata, Mikio, Suno, Manabu, Hanioka, Nobumitsu
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Animals
Glucuronidation
Glucuronides - metabolism
Glucuronosyltransferase - metabolism
Haplorhini
Humans
intestinal microsomes
Intestines - drug effects
Intestines - metabolism
Kinetics
liver microsomes
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Middle Aged
monkeys
raloxifene
Raloxifene Hydrochloride - chemistry
Raloxifene Hydrochloride - metabolism
Raloxifene Hydrochloride - pharmacology
Recombinant Proteins - metabolism
Young Adult
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Summary: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 V max values (liver microsomes, humans > monkeys; intestinal microsomes, humans  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.
ISSN:0049-8254
1366-5928
DOI:10.3109/00498254.2015.1074301