Drug-endobiotic interactions (DEIs) arise when xenobiotics affect the biosynthesis, metabolism, and transportation of endobiotics, which alter endobiotics homeostasis. Their clinical significance depends on the role of specific endobiotics in health and disease conditions. Bilirubin and bile acids are crucial endobiotics primarily metabolized by UGT1A1 and UGT1A3 enzymes. Inhibition of these enzymes by xenobiotic drugs may result in DEIs, and the current study aims to investigate this research question. Zafirlukast was identified as a pan-inhibitor for UGT1A1 and UGT1A3 isoforms, while its inhibitory potential was verified using ezetimibe, a common substrate for UGT1A1/UGT1A3. Further, serum bilirubin and plasma bile acids were compared after 7 days of exposure to Zafirlukast with vehicle control. Serum bilirubin concentrations were not altered, while the concentrations of chenodeoxycholic acid and cholic acid reduced significantly, and deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, and tauro-α/β-muricholic acid levels remained unaffected. These changes in bile acid levels may be attributed to the biosynthetic feedback or metabolic feedforward mechanisms. These results reveal that inhibition of UGT1A1/UGT1A3 enzymes by xenobiotics may potentially alter the homeostasis of bile acids and may result in clinically significant DEIs.
Mullapudi TVR, Ravi PR. Drug-endobiotic interaction effect of UGT enzymes inhibition on systemic bile acids levels in rat. J Appl Pharm Sci. 2025. Article in Press. http://doi.org/10.7324/JAPS.2025.236926
1. Sheweita SA. Drug-metabolizing enzymes mechanisms and functions. Curr Drug Meta. 2000;1(2):107-32. https://doi.org/10.2174/1389200003339117 | |
2. Di L. The role of drug metabolizing enzymes in clearance. Expert Opin Drug Meta Toxicol. 2014;10(3):379-93. https://doi.org/10.1517/17425255.2014.876006 | |
3. Muntane J. Regulation of drug metabolism and transporters. Curr Drug Metab. 2009;10(8):932-45. https://doi.org/10.2174/138920009790274595 | |
4. Krishnaswamy S, Duan SX, Von Moltke LL, Greenblatt DJ, Court MH. Validation of serotonin (5-hydroxtryptamine) as an in vitro substrate probe for human UDP-glucuronosyltransferase (UGT) 1A6. Drug Meta Dispos. 2003;31(1):133-39. https://doi.org/10.1124/dmd.31.1.133 | |
5. Wang PC, Kuchel O, Buu NT, Genest J. Catecholamine glucuronidation: an important metabolic pathway for dopamine in the rat. J Neurochem. 1983;40(5):1435-40. https://doi.org/10.1111/j.1471-4159.1983.tb13587.x | |
6. Guillemette C, Bélanger A, Lépine J. Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview. Breast Cancer Res. 2004;6(6):246. https://doi.org/10.1186/bcr936 | |
7. Bock KW. Roles of human UDP-glucuronosyltransferases in clearance and homeostasis of endogenous substrates, and functional implications. Biochem Pharmacol. 2015;96(2):77-82. https://doi.org/10.1016/j.bcp.2015.04.020 | |
8. Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG. In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos. 2005;33(11):1729-39. https://doi.org/10.1124/dmd.105.005447 | |
9. Findlay KAB, Kaptein E, Visser TJ, Burchell B. Characterization of the uridine diphosphate-glucuronosyltransferase-catalyzing thyroid hormone glucuronidation in Man1. J Clin Endocrinol Meta. 2000;85(8):2879-83. https://doi.org/10.1210/jcem.85.8.6715 | |
10. Hirashima R, Michimae H, Takemoto H, Sasaki A, Kobayashi Y, Itoh T, et al. Induction of the UDP-glucuronosyltransferase 1A1 during the perinatal period can cause neurodevelopmental toxicity. Mol Pharmacol. 2016;90(3):265-74. https://doi.org/10.1124/mol.116.104174 | |
11. Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res. 2015;56(6):1085-99. https://doi.org/10.1194/jlr.R054114 | |
12. Barbier O, Trottier J, Kaeding J, Caron P, Verreault M. Lipid-activated transcription factors control bile acid glucuronidation. Mol Cell Biochem. 2009;326(1-2):3-8. https://doi.org/10.1007/s11010-008-0001-5 | |
13. Trottier J, Perreault M, Rudkowska I, Levy C, Dallaire-Theroux A, Verreault M, et al. Profiling serum bile acid glucuronides in humans: gender divergences, genetic determinants, and response to fenofibrate. Clin Pharmacol Ther. 2013;94(4):533-43. https://doi.org/10.1038/clpt.2013.122 | |
14. McGlone ER, Bloom SR. Bile acids and the metabolic syndrome. Ann Clin Biochem. 2019;56(3):326-37. https://doi.org/10.1177/0004563218817798 | |
15. Fuchs CD, Trauner M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol. 2022;19(7):432-50. https://doi.org/10.1038/s41575-021-00566-7 | |
16. Hegade VS, Speight RA, Etherington RE, Jones DE. Novel bile acid therapeutics for the treatment of chronic liver diseases. Ther Adv Gastroenterol. 2016;9(3):376-91. https://doi.org/10.1177/1756283X16630712 | |
17. Mullapudi TVR, Ravi PR, Thipparapu G. UGT1A1 and UGT1A3 activity and inhibition in human liver and intestinal microsomes and a recombinant UGT system under similar assay conditions using selective substrates and inhibitors. Xenobiotica. 2021;51(11):1236- 46. https://doi.org/10.1080/00498254.2021.1998732 | |
18. Mullapudi TVR, Ravi PR, Thipparapu G. Simultaneous determination of seven bile acids to study the effect of ivermectin on their plasma levels in rat by UHPLC-MS/MS. J Anal Sci Technol. 2023;14(1):44. https://doi.org/10.1186/s40543-023-00408-y | |
19. Jansen PLM, Mulder GJ, Burchell B, Bock KW. New developments in glucuronidation research: Report of a workshop on "Glucuronidation, its role in health and disease." Hepatology. 1992;15(3):532-44. https://doi.org/10.1002/hep.1840150328 | |
20. Wells PG, Mackenzie PI, Chowdhury JR, Guillemette C, Gregory PA, Ishii Y, et al. Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos. 2004;32(3):281-90. https://doi.org/10.1124/dmd.32.3.281 | |
21. Xiao L, Zhang Z, Luo X. Roles of xenobiotic receptors in vascular pathophysiology. Circ J. 2014;78(7):1520-30. https://doi.org/10.1253/circj.CJ-14-0343 | |
22. Rakateli L, Huchzermeier R, van der Vorst EPC. AhR, PXR and CAR: from xenobiotic receptors to metabolic sensors. Cells. 2023;12(23):2752. https://doi.org/10.3390/cells12232752 | |
23. Li H, Wang H. Activation of xenobiotic receptors: driving into the nucleus. Expert Opin Drug Metab Toxicol. 2010;6(4):409-26. https://doi.org/10.1517/17425251003598886 | |
24. Bigo C, Caron S, Dallaire-Théroux A, Barbier O. Nuclear receptors and endobiotics glucuronidation: the good, the bad, and the UGT. Drug Meta Rev. 2013;45(1):34-47. https://doi.org/10.3109/03602532.2012.751992 | |
25. Erichsen TJ, Aehlen A, Ehmer U, Kalthoff S, Manns MP, Strassburg CP. Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids. J Hepatol. 2010;52(4):570-8. https://doi.org/10.1016/j.jhep.2010.01.010 | |
26. Trottier J, Verreault M, Grepper S, Monté D, Bélanger J, Kaeding J, et al. Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver. Hepatology. 2006;44(5):1158-70. https://doi.org/10.1002/hep.21362 | |
27. Modica S, Gadaleta RM, Moschetta A. Deciphering the nuclear bile acid receptor FXR paradigm. Nucl Recept Signal. 2010;8:e005. https://doi.org/10.1621/nrs.08005 | |
28. Jiang L, Zhang H, Xiao D, Wei H, Chen Y. Farnesoid X receptor (FXR): Structures and ligands. Comput Struct Biotechnol J. 2021;19:2148-59. https://doi.org/10.1016/j.csbj.2021.04.029 | |
29. Mahmoud HM, Elsayed Abouzed DE, Abo-Youssef AM, Hemeida RAM. Zafirlukast protects against hepatic ischemia-reperfusion injury in rats via modulating Bcl-2/Bax and NF-kappaB/SMAD-4 pathways. Int Immunopharmacol. 2023;122:110498. https://doi.org/10.1016/j.intimp.2023.110498 | |
30. Li YQ, Prentice DA, Howard ML, Mashford ML, Desmond PV. Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate-glucuronosyltransferase expression in the rat. J Gastroenterol Hepatol. 2000;15(8):865-70. https://doi.org/10.1046/j.1440-1746.2000.02223.x | |
31. van der Schoor LWE, Verkade HJ, Bertolini A, de Wit S, Mennillo E, Rettenmeier E, et al. Potential of therapeutic bile acids in the treatment of neonatal hyperbilirubinemia. Sci Rep. 2021;11(1):11107. https://doi.org/10.1038/s41598-021-90687-5 | |
32. Sugatani J. Function, genetic polymorphism, and transcriptional regulation of human UDP-glucuronosyltransferase (UGT) 1A1. Drug Metab Pharmacokinet. 2013;28(2):83-92. https://doi.org/10.2133/dmpk.DMPK-12-RV-096 | |
33. Oda S, Fujiwara R, Kutsuno Y, Fukami T, Itoh T, Yokoi T, et al. Targeted screen for human UDP-glucuronosyltransferases inhibitors and the evaluation of potential drug-drug interactions with zafirlukast. Drug Metab Dispos. 2015;43(6):812-8. https://doi.org/10.1124/dmd.114.062141 | |
34. Schierle S, Helmstädter M, Schmidt J, Hartmann M, Horz M, Kaiser A, et al. Dual farnesoid X receptor/soluble epoxide hydrolase modulators derived from zafirlukast. ChemMedChem. 2020;15(1):50-67. https://doi.org/10.1002/cmdc.201900576 | |
35. Gobel T, Diehl O, Heering J, Merk D, Angioni C, Wittmann SK, et al. Zafirlukast is a dual modulator of human soluble epoxide hydrolase and peroxisome proliferator-activated receptor gamma. Front Pharmacol. 2019;10:263. https://doi.org/10.3389/fphar.2019.00263 | |
36. Gelzinis JA, Szahaj MK, Bekendam RH, Wurl SE, Pantos MM, Verbetsky CA, et al. Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic. FASEB J. 2023;37(5):e22914. https://doi.org/10.1096/fj.202201952R | |
Year
Month