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.

In Vitro Metabolism of Auriculasin and Its Inhibitory Effects on Human Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes

“…K i reflects the affinity of an inhibitor for its target enzyme, and the lower the K i , the stronger the inhibitory effect on the target enzyme . DDI was therefore possible when auriculasin was coadminstrated with CYP3A4 substrates (e.g., ibrutinib and atorvastatin), , CYP2C9 substrates (e.g., warfarin and phenytoin), or UGT1A8 substrates (e.g., raloxifene) . Molecular docking was used to explore the molecular mechanism of interactions between auriculasin and CYPs.…”

“…32 DDI was therefore possible when auriculasin was coadminstrated with CYP3A4 substrates (e.g., ibrutinib and atorvastatin), 33,34 CYP2C9 substrates (e.g., warfarin and phenytoin), 35 or UGT1A8 substrates (e.g., raloxifene). 36 Molecular docking was used to explore the molecular mechanism of interactions between auriculasin and CYPs. Due to the small binding pockets in CYP1A2 and CYP2E1, auriculasin did not bind to the desired binding pockets, which was consistent with the results for auriculasin incubation with recombined CPY1A2 and CYP2E1.…”

Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9 and 2B7 and Impacts on Glucuronidation Activity

“…With respect to substrate selectivity, UGT enzymes display distinct, but overlapping functions. Representative substrates of UGT1A1 include bilirubin, ethynylestradiol, raloxifene, and irinotecan456. Meanwhile, estrone, mycophenolic acid, raloxifene and retinoic acid are typical substrates for UGT1A95789.…”

“…Representative substrates of UGT1A1 include bilirubin, ethynylestradiol, raloxifene, and irinotecan456. Meanwhile, estrone, mycophenolic acid, raloxifene and retinoic acid are typical substrates for UGT1A95789. UGT2B7 is known as the most important human UGT enzyme responsible for phase II metabolism of most clinically used drugs, including morphine, zidovudine, and carbamazepine10111213.…”