TY - JOUR
T1 - Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys
T2 - Contribution of UGT1A1, UGT1A8 and UGT1A9
AU - Kishi, Naoki
AU - Takasuka, Akane
AU - Kokawa, Yuki
AU - Isobe, Takashi
AU - Taguchi, Maho
AU - Shigeyama, Masato
AU - Murata, Mikio
AU - Suno, Manabu
AU - Hanioka, Nobumitsu
PY - 2016/4/2
Y1 - 2016/4/2
N2 - 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 Km and CLint 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 Km or S50, Vmax and CLint 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.
AB - 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 Km and CLint 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 Km or S50, Vmax and CLint 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.
KW - Glucuronidation
KW - humans
KW - intestinal microsomes
KW - liver microsomes
KW - monkeys
KW - raloxifene
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U2 - 10.3109/00498254.2015.1074301
DO - 10.3109/00498254.2015.1074301
M3 - Article
C2 - 26247833
AN - SCOPUS:84956939513
SN - 0049-8254
VL - 46
SP - 289
EP - 295
JO - Xenobiotica
JF - Xenobiotica
IS - 4
ER -