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Drug Metabolism and Bioanalysis Letters

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ISSN (Print): 2949-6810
ISSN (Online): 2949-6829

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Research Article

ZY12201: A Potent TGR5 Agonist: Identification of a Novel Pan CYP450 Inhibitor Tool Compound for In-Vitro Assessment

Author(s): Poonam Giri*, Lakshmikant Gupta, Anil Rathod, Vipul Joshi, Shyamkumar Giri, Nirmal Patel, Sameer Agarwal and Mukul R Jain

Volume 15, Issue 2, 2022

Published on: 05 July, 2022

Page: [116 - 132] Pages: 17

DOI: 10.2174/1872312815666220315145945

Price: $65

Abstract

Background: Identification of clinical Drug-Drug Interaction (DDI) risk is an important aspect of drug discovery and development owing to poly-pharmacy in present-day clinical therapy. Drug Metabolizing Enzymes (DME) play important roles in the efficacy and safety of drug candidates. Hence, the evaluation of a New Chemical Entity (NCE) as a victim or perpetrator is very crucial for DDI risk mitigation. ZY12201 (2-((2-(4-(1H-imidazol-1-yl) phenoxy) ethyl) thio)-5-(2- (3, 4-dimethoxy phenyl) propane-2-yl)-1-(4-fluorophenyl)-1H-imidazole) is a novel and potent Takeda-G-protein-receptor-5 (TGR-5) agonist. ZY12201 was evaluated in-vitro to investigate the DDI liabilities.

Objective: The key objective was to evaluate the CYP inhibition potential of ZY12201 for an opportunity to use it as a tool compound for pan CYP inhibition activities.

Methods: In-vitro Drug-Metabolizing Enzyme (DME) inhibition potential of ZY12201 was evaluated against major CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5), Aldehyde Oxidase (AO), Monoamine Oxidase (MAO), and Flavin-containing Monooxygenase (FMO) in human liver cytosol/mitochondrial preparation/microsomes using probe substrates and Liquid Chromatography with tandem Mass Spectrometry (LC-MS-MS) method).

Results: It was found that the study conducted on ZY12201 at 100 μM ZY12201 showed a reduction in the metabolism of vanillin (AO probe substrate), tryptamine (MAO probe substrate), and benzydamine (FMO probe substrate) by 49.2%, 14.7%, and 34.9%, respectively. ZY12201 Ki values were 0.38, 0.25, 0.07, 0.01, 0.06, 0.02, 7.13, 0.03 and 0.003 μM for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 (substrate: testosterone) and CYP3A4/5 (substrate: midazolam), respectively. Time-dependant CYP inhibition potential of ZY12201 was assessed against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5, and no apparent IC50 shift was observed.

Conclusion: ZY12201, at 100 μM concentration, showed low inhibition potential of AO, MAO, and FMO. ZY12201 was found as a potent inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 while moderately inhibiting CYP2E1. Inhibition of CYP1A2, CYP2B6, CYP2C19, and CYP2E1 by ZY12201 was competitive, while the inhibition of CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5 was of mixed-mode. ZY12201 is a non-time-dependent inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5.

In summary, the reported Ki values unequivocally support that ZY12201 has a high potential to inhibit all major CYP isoforms. ZY12201 can be effectively used as a tool compound for in-vitro evaluation of CYP-based metabolic contribution to total drug clearance in the lead optimization stage of drug discovery research.

Keywords: Direct CYP inhibitor, time-dependent CYP inhibitor, drug-drug interaction (DDI), human liver microsomes, cytosol, mitochondrial preparation, LC-MS/MS.

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[1]
Phang-Lyn, S.; Llerena, V.A. Biochemistry, Biotransformation; StatPearls Publishing: Treasure Island, FL, 2021. [https://www.ncbi.nlm.nih.gov/books/NBK544353/]
[2]
Xie, F.; Ding, X.; Zhang, Q.Y. An update on the role of intestinal cytochrome P450 enzymes in drug disposition. Acta Pharm. Sin. B, 2016, 6(5), 374-383.
[http://dx.doi.org/10.1016/j.apsb.2016.07.012] [PMID: 27709006]
[3]
Rendic, S. Summary of information on human CYP enzymes: Human P450 metabolism data. Drug Metab. Rev., 2002, 34(1-2), 83-448.
[http://dx.doi.org/10.1081/DMR-120001392] [PMID: 11996015]
[4]
Dahlinger, D.; Duechting, S.; Nuecken, D.; Sydow, K.; Fuhr, U.; Frechen, S. Development and validation of an in vitro, seven-in-one human cytochrome P450 assay for evaluation of both direct and time-dependent inhibition. J. Pharmacol. Toxicol. Methods, 2016, 77, 66-75.
[http://dx.doi.org/10.1016/j.vascn.2015.10.003] [PMID: 26528794]
[5]
Arora, S.; Taneja, I.; Challagundla, M.; Raju, K.S.; Singh, S.P.; Wahajuddin, M. In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data. Toxicol. Lett., 2015, 239(1), 1-8.
[http://dx.doi.org/10.1016/j.toxlet.2015.08.202] [PMID: 26278343]
[6]
Daly, A.K. Pharmacogenetics of the cytochromes P450. Curr. Top. Med. Chem., 2004, 4(16), 1733-1744.
[http://dx.doi.org/10.2174/1568026043387070] [PMID: 15579105]
[7]
Ingelman-Sundberg, M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: The past, present and future. Trends Pharmacol. Sci., 2004, 25(4), 193-200.
[http://dx.doi.org/10.1016/j.tips.2004.02.007] [PMID: 15063083]
[8]
Wilkinson, G.R. Drug metabolism and variability among patients in drug response. N. Engl. J. Med., 2005, 352(21), 2211-2221.
[http://dx.doi.org/10.1056/NEJMra032424] [PMID: 15917386]
[9]
Giri, P.; Gupta, L.; Singh, S.; Patel, N.; Srinivas, N.R.; Srivastva, B.K.; Desai, R.C.; Patel, P.R. Assessment of the in vitro cytochrome P450 (CYP) inhibition potential of ZYTP1, a novel poly (ADP-ribose) polymerase inhibitor. Xenobiotica, 2019, 49(10), 1164-1172.
[http://dx.doi.org/10.1080/00498254.2018.1546916] [PMID: 30488748]
[10]
Williams, J.A.; Hurst, S.I.; Bauman, J.; Jones, B.C.; Hyland, R.; Gibbs, J.P.; Obach, R.S.; Ball, S.E. Reaction phenotyping in drug discovery: Moving forward with confidence? Curr. Drug Metab., 2003, 4(6), 527-534.
[http://dx.doi.org/10.2174/1389200033489235] [PMID: 14683480]
[11]
Zhang, H.; Davis, C.D.; Sinz, M.W.; Rodrigues, A.D. Cytochrome P450 reaction-phenotyping: An industrial perspective. Expert Opin. Drug Metab. Toxicol., 2007, 3(5), 667-687.
[http://dx.doi.org/10.1517/17425255.3.5.667] [PMID: 17916054]
[12]
Srinivas, N.R.; Mullangi, R. Bioanalysis in oncology drug discovery. Biomarkers Med., 2015, 9(9), 877-886.
[http://dx.doi.org/10.2217/bmm.15.65] [PMID: 26328779]
[13]
Coutant, D.E.; Hall, S.D. Disease-drug interactions in inflammatory states via effects on CYP-mediated drug clearance. J. Clin. Pharmacol., 2018, 58(7), 849-863.
[http://dx.doi.org/10.1002/jcph.1093] [PMID: 29505093]
[14]
Bahar, M.A.; Setiawan, D.; Hak, E.; Wilffert, B. Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: A systematic review on CYP2C9, CYP2C19 and CYP2D6. Pharmacogenomics, 2017, 18(7), 701-739.
[http://dx.doi.org/10.2217/pgs-2017-0194] [PMID: 28480783]
[15]
Dash, R.P.; Babu, R.J.; Srinivas, N.R. Reappraisal and perspectives of clinical drug-drug interaction potential of α-glucosidase inhibitors such as acarbose, voglibose and miglitol in the treatment of type 2 diabetes mellitus. Xenobiotica, 2018, 48(1), 89-108.
[http://dx.doi.org/10.1080/00498254.2016.1275063] [PMID: 28010166]
[16]
Dash, R.P.; Rais, R.; Srinivas, N.R. Key pharmacokinetic essentials of fixed-dosed combination products: Case studies and perspectives. Clin. Pharmacokinet., 2018, 57(4), 419-426.
[http://dx.doi.org/10.1007/s40262-017-0589-2] [PMID: 28791593]
[17]
Srinivas, N.R. Cranberry juice ingestion and clinical drug-drug interaction potentials; review of case studies and perspectives. J. Pharm. Pharm. Sci., 2013, 16(2), 289-303.
[http://dx.doi.org/10.18433/J3NG6Z] [PMID: 23958198]
[18]
Srinivas, N.R. Pharmacokinetic interaction of rifampicin with oral versus intravenous anticancer drugs: Challenges, dilemmas and paradoxical effects due to multiple mechanisms. Drugs R D., 2016, 16(2), 141-148.
[http://dx.doi.org/10.1007/s40268-016-0133-0] [PMID: 27098526]
[19]
Di, L. Reaction phenotyping to assess victim drug-drug interaction risks. Expert Opin. Drug Discov., 2017, 12(11), 1105-1115.
[http://dx.doi.org/10.1080/17460441.2017.1367280] [PMID: 28820269]
[20]
Tan, B.H.; Pan, Y.; Dong, A.N.; Ong, C.E. In vitro and in silico approaches to study Cytochrome P450-mediated interactions. J. Pharm. Pharm. Sci., 2017, 20(1), 319-328.
[http://dx.doi.org/10.18433/J3434R] [PMID: 29145931]
[21]
Tornio, A.; Backman, J.T. Cytochrome P450 in pharmacogenetics: An update. Adv. Pharmacol., 2018, 83, 3-32.
[http://dx.doi.org/10.1016/bs.apha.2018.04.007] [PMID: 29801580]
[22]
UDFDA guidance. In vitro drug interaction studies — cytochrome P450 enzyme- and transporter-mediated drug interactions guidance for industry. 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions
[23]
Giri, P.; Gupta, L.; Naidu, S.; Joshi, V.; Patel, N.; Giri, S.; Srinivas, N.R. In vitro drug-drug interaction potential of sulfoxide and/or sulfone metabolites of albendazole, triclabendazole, aldicarb, methiocarb, montelukast and ziprasidone. Drug Metab. Lett., 2018, 12(2), 101-116.
[http://dx.doi.org/10.2174/1872312812666180816164626] [PMID: 30117405]
[24]
Giri, P.; Naidu, S.; Patel, N.; Patel, H.; Srinivas, N.R. Evaluation of in vitro cytochrome P450 inhibition and in vitro fate of structurally diverse N-oxide metabolites: Case studies with clozapine, levofloxacin, roflumilast, voriconazole and zopiclone. Eur. J. Drug Metab. Pharmacokinet., 2017, 42(4), 677-688.
[http://dx.doi.org/10.1007/s13318-016-0385-7] [PMID: 27853934]
[25]
Agarwal, S.; Patil, A.; Aware, U.; Deshmukh, P.; Darji, B.; Sasane, S.; Sairam, K.V.; Priyadarsiny, P.; Giri, P.; Patel, H.; Giri, S.; Jain, M.; Desai, R.C. Discovery of a potent and orally efficacious TGR5 receptor agonist. ACS Med. Chem. Lett., 2015, 7(1), 51-55.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00323] [PMID: 26819665]
[26]
Joshi, V.M.; Sojitra, C.; Sasane, S.; Shukla, M.; Chauhana, R.; Chaubey, V.; Jain, S.; Shah, K.; Mande, H.; Soman, S.; Sudhakar, P.; Shah, S.R.; Pandey, B.; Singh, K.K.; Agarwal, S. Practical and efficient synthesis of 2-Thio-imidazole derivative - ZY12201: A potent TGR5 agonist. Org. Process Res. Dev., 2020, 24(8), 1508-1514.
[http://dx.doi.org/10.1021/acs.oprd.0c00234]
[27]
Sojitra, C.; Dholakia, C.; Sudhakar, P.; Singh, K.K.; Agarwal, S. Identification of degradation impurity of TGR5 receptor agonist-ZY12201 by LC-MS technique during force degradation study. SN Appl. Sci., 2021, 3(6), 660.
[http://dx.doi.org/10.1007/s42452-021-04660-y] [PMID: 34056545]
[28]
Jones, B.C.; Srivastava, A.; Colclough, N.; Wilson, J.; Reddy, V.P.; Amberntsson, S.; Li, D. An investigation into the prediction of in vivo clearance for a range of flavin-containing monooxygenase substrates. Drug Metab. Dispos., 2017, 45(10), 1060-1067.
[http://dx.doi.org/10.1124/dmd.117.077396] [PMID: 28784689]
[29]
Li, G.; Huang, K.; Nikolic, D.; van Breemen, R.B. High-throughput cytochrome P450 cocktail inhibition assay for assessing drug-drug and drug-botanical interactions. Drug Metab. Dispos., 2015, 43(11), 1670-1678.
[http://dx.doi.org/10.1124/dmd.115.065987] [PMID: 26285764]
[30]
Ideura, T.; Muramatsu, T.; Higuchi, M.; Tachibana, N.; Hora, K.; Kiyosawa, K. Tacrolimus/itraconazole interactions: A case report of ABO-incompatible living-related renal transplantation. Nephrol. Dial. Transplant., 2000, 15(10), 1721-1723.
[http://dx.doi.org/10.1093/ndt/15.10.1721] [PMID: 11007866]
[31]
Chonlahan, J.; Halloran, M.A.; Hammonds, A. Leflunomide and warfarin interaction: Case report and review of the literature. Pharmacotherapy, 2006, 26(6), 868-871.
[http://dx.doi.org/10.1592/phco.26.6.868] [PMID: 16716139]
[32]
Rao Gajula, S.N.; Pillai, M.S.; Samanthula, G.; Sonti, R. Cytochrome P450 enzymes: A review on drug metabolizing enzyme inhibition studies in drug discovery and development. Bioanalysis, 2021, 13(17), 1355-1378.
[http://dx.doi.org/10.4155/bio-2021-0132] [PMID: 34517735]
[33]
Lu, C.; Di, L. In vitro and in vivo methods to assess pharmacokinetic drug- drug interactions in drug discovery and development. Biopharm. Drug Dispos., 2020, 41(1-2), 3-31.
[http://dx.doi.org/10.1002/bdd.2212] [PMID: 31778578]
[34]
Peng, Y.; Cheng, Z.; Xie, F. Evaluation of pharmacokinetic drug-drug interactions: A review of the mechanisms, in vitro and in silico approaches. Metabolites, 2021, 11(2), 75.
[http://dx.doi.org/10.3390/metabo11020075] [PMID: 33513941]
[35]
Min, J.S.; Bae, S.K. Prediction of drug-drug interaction potential using physiologically based pharmacokinetic modeling. Arch. Pharm. Res., 2017, 40(12), 1356-1379.
[http://dx.doi.org/10.1007/s12272-017-0976-0] [PMID: 29079968]
[36]
Kato, H. Computational prediction of cytochrome P450 inhibition and induction. Drug Metab. Pharmacokinet., 2020, 35(1), 30-44.
[http://dx.doi.org/10.1016/j.dmpk.2019.11.006] [PMID: 31902468]
[37]
Giri, P.; Patel, H.; Srinivas, N.R. Use of cocktail probe drugs for indexing cytochrome P450 enzymes in clinical pharmacology studies - review of case studies. Drug Metab. Lett., 2019, 13(1), 3-18.
[http://dx.doi.org/10.2174/1872312812666181119154734] [PMID: 30451124]
[38]
Wang, J.; Chen, F.; Jiang, H.; Xu, J.; Meng, D.; Geng, P.; Dai, D.; Hu, J.; Zhou, Y.; Zhou, Q.; Wang, S. Inhibition and induction by poziotinib of different rat cytochrome P450 enzymes in vivo and in an in vitro cocktail method. Front. Pharmacol., 2021, 11, 593518.
[http://dx.doi.org/10.3389/fphar.2020.593518] [PMID: 33746741]
[39]
Linder, C.D.; Renaud, N.A.; Hutzler, J.M. Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab. Dispos., 2009, 37(1), 10-13.
[http://dx.doi.org/10.1124/dmd.108.024075] [PMID: 18936109]
[40]
Sun, Q.; Harper, T.W.; Dierks, E.A.; Zhang, L.; Chang, S.; Rodrigues, A.D.; Marathe, P. 1-Aminobenzotriazole, a known cytochrome P450 inhibitor, is a substrate and inhibitor of N-acetyltransferase. Drug Metab. Dispos., 2011, 39(9), 1674-1679.
[http://dx.doi.org/10.1124/dmd.111.039834] [PMID: 21677062]
[41]
Chen, A.; Zhou, X.; Tang, S.; Liu, M.; Wang, X. Evaluation of the inhibition potential of plumbagin against cytochrome P450 using LC-MS/MS and cocktail approach. Sci. Rep., 2016, 28482, 1-12.
[http://dx.doi.org/10.1038/srep28482]

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