Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5547191 | Drug Metabolism and Pharmacokinetics | 2016 | 8 Pages |
Abstract
This study aims to characterize the glucuronidation kinetics of ursolic acid (UA) in human liver microsomes (HLMs) and intestinal microsomes (HIMs) and identify the main UDP-glucuronosyltransferases (UGTs) involved. In our present study, only one type of UA glucuronide was observed after incubation with HLMs and HIMs respectively and was identified as a UA hydroxyl O-glucuronide. The glucuronidation of UA can be shown in HLMs and HIMs with Km values of 3.29 ± 0.16 and 3.74 ± 0.22 μM and Vmax values of 0.33 ± 0.03 and 0.42 ± 0.03 nmol/min/(mg protein). Among the 12 recombinant UGT enzymes investigated, UGT1A3 and UGT1A4 were identified as the major enzymes catalyzing the glucuronidation of UA [Km values of 2.58 ± 0.12 and 4.66 ± 0.60 μM, Vmax values of 0.72 ± 0.01 and 1.00 ± 0.06 nmol/min/(mg protein)]. The chemical inhibition study showed that the IC50 for hecogenin inhibition of UA glucuronidation was 51.79 ± 4.32 μM in HLMs. And chenodeoxycholic acid inhibited UA glucuronidation in HLMs with an IC50 of 28.26 ± 2.91 μM. In addition, UA glucuronidation in a panel of eight HLM was significantly correlated with telmisartan glucuronidation (r2 = 0.7660, p < 0.01) and trifluoperazine glucuronidation (r2 = 0.5866, p < 0.01) respectively. These findings collectively indicate that UGT1A3 and UGT1A4 were the main enzymes responsible for the glucuronidation of UA in human.
Keywords
RILDESIMetabolism pathwayUDPGAUGTsDDILC-MSVmaxnuclear magnetic resonanceHLMsLC-MS/MSm/zUDP-glucuronosyltransferasesUDP-glucuronic acidUrsolic acidstandard deviationNMRDrug–drug interactionsmaximum velocitySIMLiquid chromatography mass spectrometryLiquid chromatography-tandem mass spectrometryHuman Liver Microsomesmass to charge ratioIntrinsic clearanceClint
Related Topics
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Authors
Rui Gao, Mingyi Liu, Yu Chen, Chunhua Xia, Hong Zhang, Yuqing Xiong, Shibo Huang,