535 FXR-Mediated Regulation of the Human Hepatic Bile Acid Udp-Glucuronosyltransferase (Ugt) 1a3 Gene in Cholestasis

Erichsen, Thomas; Aehlen, A.; Ehmer, Ursula; Lankisch, Tim O.; Manns, MP; Strassburg, Christian P.

doi:10.1016/s0168-8278(08)60537-1

Journal of Hepatology

2008

DOI: 10.1016/s0168-8278(08)60537-1

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535 FXR-Mediated Regulation of the Human Hepatic Bile Acid Udp-Glucuronosyltransferase (Ugt) 1a3 Gene in Cholestasis

Thomas Erichsen¹,

A. Aehlen²,

Ursula Ehmer³

et al.

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Inhibition of human UDP‐glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug–drug interactions

Wang

Jia

et al. 2020

Biopharm & Drug Disp

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Cancer therapy with tyrosine kinase inhibitors (TKIs) is a rapidly developing field, and several TKIs have been reported to have an impact on the activities of UDP‐glucosyltransferases (UGTs), implying a potential risk for drug–drug interaction (DDI). Herein, we investigated the inhibitory effects of two commonly used TKIs, midostaurin and ruxolitinib, on human UGTs and quantitatively evaluated their DDI potential via UGT inhibition. It was found that midostaurin was a potent inhibitor of the majority of human UGTs, including UGT1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15, and 2B17, with IC50 values lower than 4 μM (IC50 0.0128–3.85 μM), while ruxolitinib exhibited weak inhibition towards the activity of almost all the tested UGT isoforms. Furthermore, based on reversible inhibition, the co‐administration of midostaurin at the clinical available dose was predicted to increase the plasma exposure to sensitive UGT1A3, 1A7, and 1A8 substrates by at least 61.4%, 25.6%, and 651%, respectively. In summary, our data identify that midostaurin is a potent inhibitor of the majority of human UGTs and may bring a potential risk of DDI via inhibition against UGT1A3, 1A7, and 1A8, while ruxolitinib cannot trigger UGT‐mediated DDI due to its weak inhibition towards UGTs.

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Inhibition of human UDP‐glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug–drug interactions

Wang

Jia

et al. 2020

Biopharm & Drug Disp

View full text Add to dashboard Cite

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Cabozantinib Carries the Risk of Drug-Drug Interactions via Inhibition of UDPglucuronosyltransferase (UGT) 1A9

Wang

Jiang

Wang

et al. 2022

CDM

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Background: Cabozantinib is a multiple receptor tyrosine kinases inhibitor (TKI) approved to treat progressive, metastatic medullary thyroid cancer, advanced renal cell carcinoma and hepatocellular carcinoma. Drug-drug interactions (DDIs) for cabozantinib have been identified involving the role of cytochromes P450. Although previous study revealed cabozantinib showed a slight inhibition of UDP-glucuronosyltransferase (UGT) 1A1 at the highest concentration tested, there are no reports on the potential for UGTs mediated-DDIs and so the current study seeks to address that knowledge gap. Purpose: This study aimed to investigate the inhibitory effect of cabozantinib on human UGTs and to quantitatively evaluate the DDI potential via UGT inhibition. Methods: The inhibitory effects of cabozantinib on UGTs were determined by measuring the formation rates for 4-methylumbelliferone (4-MU) glucuronide and trifluoperazine N-glucuronide using recombinant human UGT isoforms in the absence or presence of cabozantinib. Inhibition kinetic studies were conducted to determine the type of inhibition of cabozantinib on UGTs and the corresponding inhibition constant (Ki) value. In vitro-in vivo extrapolation (IVIVE) was further employed to predict the potential risk of DDI in vivo. Results: Cabozantinib displayed potent inhibition of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15. Cabozantinib exhibited the noncompetitive inhibition towards UGT1A1 and 1A3, and inhibition towards UGT1A7 and 1A9. The Ki,u values (mean ± standard deviation) were calculated to be 2.15±0.11 μM, 0.83±0.05 μM, 0.75±0.04 μM and 0.18±0.10 μM for UGT1A1, 1A3, 1A7 and 1A9, respectively. Co-administration of cabozantinib at the clinically approved dose of 60 mg/day or 140 mg/day may result in approximately 26% to 60% increase in the systemic exposure of drugs predominantly cleared by UGT1A9, implying high risk of DDIs. Conclusion: Cabozantinib has the potential to cause DDIs via the inhibition of UGT1A9 and additional attention should be paid to the safety of the combined use of cabozantinib and drugs metabolized by UGT1A9.

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535 FXR-Mediated Regulation of the Human Hepatic Bile Acid Udp-Glucuronosyltransferase (Ugt) 1a3 Gene in Cholestasis

Cited by 2 publications

References 0 publications

Inhibition of human UDP‐glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug–drug interactions

Inhibition of human UDP‐glucuronosyltransferase enzymes by midostaurin and ruxolitinib: implications for drug–drug interactions

Cabozantinib Carries the Risk of Drug-Drug Interactions via Inhibition of UDPglucuronosyltransferase (UGT) 1A9

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