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Predicting Intrinsic Clearance for Drugs and Drug Candidates Metabolized by Aldehyde Oxidase

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Department of Chemistry, Washington State University, Pullman, Washington 99163, United States
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States
*Tel: 509-592-8790. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2013, 10, 4, 1262–1268
Publication Date (Web):January 30, 2013
https://doi.org/10.1021/mp300568r
Copyright © 2013 American Chemical Society
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    Abstract

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    Metabolism by aldehyde oxidase (AO) has been responsible for a number of drug failures in clinical trials. The main reason is the clearance values for drugs metabolized by AO are underestimated by allometric scaling from preclinical species. Furthermore, in vitro human data also underestimates clearance. We have developed the first in silico models to predict both in vitro and in vivo human intrinsic clearance for 8 drugs with just two chemical descriptors. These models explain a large amount of the variance in the data using two computational estimates of the electronic and steric features of the reaction. The in vivo computational models for human metabolism are better than in vitro preclinical animal testing at predicting human intrinsic clearance. Thus, it appears that AO is amenable to computational prediction of rates, which may be used to guide drug discovery, and predict pharmacokinetics for clinical trials.

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    Figures describing the steric interaction model and Cartesian coordinates for all the calculated structures. This material is available free of charge via the Internet at http://pubs.acs.org.

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    2. Jihui Zhao, Rongrong Cui, Lihao Wang, Yingjia Chen, Zunyun Fu, Xiaoyu Ding, Chen Cui, Tianbiao Yang, Xutong Li, Yuan Xu, Kaixian Chen, Xiaomin Luo, Hualiang Jiang, Mingyue Zheng. Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model. Journal of Medicinal Chemistry 2020, 63 (12) , 6523-6537. https://doi.org/10.1021/acs.jmedchem.9b01895
    3. Nenad Manevski, Lloyd King, William R. Pitt, Fabien Lecomte, Francesca Toselli. Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery. Journal of Medicinal Chemistry 2019, 62 (24) , 10955-10994. https://doi.org/10.1021/acs.jmedchem.9b00875
    4. Marco Montefiori, Flemming Steen Jørgensen, and Lars Olsen . Aldehyde Oxidase: Reaction Mechanism and Prediction of Site of Metabolism. ACS Omega 2017, 2 (8) , 4237-4244. https://doi.org/10.1021/acsomega.7b00658
    5. Erickson M. Paragas, Sara C. Humphreys, Joshua Min, Carolyn A. Joswig-Jones, Silke Leimkühler, and Jeffrey P. Jones . ecoAO: A Simple System for the Study of Human Aldehyde Oxidases Role in Drug Metabolism. ACS Omega 2017, 2 (8) , 4820-4827. https://doi.org/10.1021/acsomega.7b01054
    6. Yuan Xu, Liang Li, Yulan Wang, Jing Xing, Lei Zhou, Dafang Zhong, Xiaomin Luo, Hualiang Jiang, Kaixian Chen, Mingyue Zheng, Pan Deng, and Xiaoyan Chen . Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: A Combined Computational and Experimental Study. Journal of Medicinal Chemistry 2017, 60 (7) , 2973-2982. https://doi.org/10.1021/acs.jmedchem.7b00019
    7. Fionn O’Hara, Aaron C. Burns, Michael R. Collins, Deepak Dalvie, Martha A. Ornelas, Alfin D. N. Vaz, Yuta Fujiwara, and Phil S. Baran . A Simple Litmus Test for Aldehyde Oxidase Metabolism of Heteroarenes. Journal of Medicinal Chemistry 2014, 57 (4) , 1616-1620. https://doi.org/10.1021/jm4017976
    8. John T. Barr, Jeffrey P. Jones, Carolyn A. Joswig-Jones, and Dan A. Rock . Absolute Quantification of Aldehyde Oxidase Protein in Human Liver Using Liquid Chromatography–Tandem Mass Spectrometry. Molecular Pharmaceutics 2013, 10 (10) , 3842-3849. https://doi.org/10.1021/mp4003046
    9. Yuto Shiotake, Yu Takano, Toru Saito. Semi-empirical and machine learning-based prediction of site of metabolisms mediated by aldehyde oxidase. Chemical Physics Letters 2023, 833 , 140942. https://doi.org/10.1016/j.cplett.2023.140942
    10. Xiaoyan Pang, Chongzhuang Tang, Runcong Guo, Xiaoyan Chen. Non-cytochrome P450 enzymes involved in the oxidative metabolism of xenobiotics: Focus on the regulation of gene expression and enzyme activity. Pharmacology & Therapeutics 2022, 233 , 108020. https://doi.org/10.1016/j.pharmthera.2021.108020
    11. S. Cyrus Khojasteh, Harvey Wong, Donglu Zhang, Cornelis E.C.A. Hop. DMPK Lead Optimization. 2022, 63-139. https://doi.org/10.1007/978-3-031-10691-0_3
    12. Agnes Nuo Han, Beatrice Rae Han, Tao Zhang, Tycho Heimbach. Hepatic Impairment Physiologically Based Pharmacokinetic Model Development: Current Challenges. Current Pharmacology Reports 2021, 7 (6) , 213-226. https://doi.org/10.1007/s40495-021-00266-5
    13. Somaieh Soltani, Somayeh Hallaj-Nezhadi, Mohammad Reza Rashidi. A comprehensive review of in silico approaches for the prediction and modulation of aldehyde oxidase-mediated drug metabolism: The current features, challenges and future perspectives. European Journal of Medicinal Chemistry 2021, 222 , 113559. https://doi.org/10.1016/j.ejmech.2021.113559
    14. David C. Pryde, Dharmendra B. Yadav, Rajib Ghosh. Aldehyde and Xanthine Oxidase Metabolism. 2021, 248-277. https://doi.org/10.1039/9781788016414-00248
    15. Pranav Shah, Vishal B. Siramshetty, Alexey V. Zakharov, Noel T. Southall, Xin Xu, Dac-Trung Nguyen. Predicting liver cytosol stability of small molecules. Journal of Cheminformatics 2020, 12 (1) https://doi.org/10.1186/s13321-020-00426-7
    16. Phillip R. Lazzara, Terry W. Moore. Scaffold-hopping as a strategy to address metabolic liabilities of aromatic compounds. RSC Medicinal Chemistry 2020, 11 (1) , 18-29. https://doi.org/10.1039/C9MD00396G
    17. Christine Beedham. Aldehyde oxidase; new approaches to old problems. Xenobiotica 2020, 50 (1) , 34-50. https://doi.org/10.1080/00498254.2019.1626029
    18. Narges Cheshmazar, Siavoush Dastmalchi, Mineko Terao, Enrico Garattini, Maryam Hamzeh-Mivehroud. Aldehyde oxidase at the crossroad of metabolism and preclinical screening. Drug Metabolism Reviews 2019, 51 (4) , 428-452. https://doi.org/10.1080/03602532.2019.1667379
    19. Deepak Dalvie, Li Di. Aldehyde oxidase and its role as a drug metabolizing enzyme. Pharmacology & Therapeutics 2019, 201 , 137-180. https://doi.org/10.1016/j.pharmthera.2019.05.011
    20. Armina Abbasi, Erickson M. Paragas, Carolyn A. Joswig-Jones, John T. Rodgers, Jeffrey P. Jones. Time Course of Aldehyde Oxidase and Why It Is Nonlinear. Drug Metabolism and Disposition 2019, 47 (5) , 473-483. https://doi.org/10.1124/dmd.118.085787
    21. Haruka Nishimuta, Takao Watanabe, Kiyoko Bando. Quantitative Prediction of Human Hepatic Clearance for P450 and Non-P450 Substrates from In Vivo Monkey Pharmacokinetics Study and In Vitro Metabolic Stability Tests Using Hepatocytes. The AAPS Journal 2019, 21 (2) https://doi.org/10.1208/s12248-019-0294-1
    22. Marco Montefiori, Casper Lyngholm-Kjærby, Anthony Long, Lars Olsen, Flemming Steen Jørgensen. Fast Methods for Prediction of Aldehyde Oxidase-Mediated Site-of-Metabolism. Computational and Structural Biotechnology Journal 2019, 17 , 345-351. https://doi.org/10.1016/j.csbj.2019.03.003
    23. Jiang Wei Zhang, Wen Xiao, Zhen Ting Gao, Zheng Tian Yu, Ji Yue (Jeff) Zhang. Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect. Drug Metabolism and Disposition 2018, 46 (12) , 1847-1855. https://doi.org/10.1124/dmd.118.081919
    24. Cristiano Mota, Catarina Coelho, Silke Leimkühler, Enrico Garattini, Mineko Terao, Teresa Santos-Silva, Maria João Romão. Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics. Coordination Chemistry Reviews 2018, 368 , 35-59. https://doi.org/10.1016/j.ccr.2018.04.006
    25. Raj Kumar, Gaurav Joshi, Harveen Kler, Sourav Kalra, Manpreet Kaur, Ramandeep Arya. Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases. Medicinal Research Reviews 2018, 38 (4) , 1073-1125. https://doi.org/10.1002/med.21457
    26. Ryan A. Dick. Refinement of In Vitro Methods for Identification of Aldehyde Oxidase Substrates Reveals Metabolites of Kinase Inhibitors. Drug Metabolism and Disposition 2018, 46 (6) , 846-859. https://doi.org/10.1124/dmd.118.080960
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    28. Rachel D. Crouch, Anna L. Blobaum, Andrew S. Felts, P. Jeffrey Conn, Craig W. Lindsley. Species-Specific Involvement of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of the Pyrimidine-Containing mGlu 5 -Negative Allosteric Modulator VU0424238 (Auglurant). Drug Metabolism and Disposition 2017, 45 (12) , 1245-1259. https://doi.org/10.1124/dmd.117.077552
    29. David J. Wilkinson, Rosalind L. Southall, Mingguang Li, Lisa M. Wright, Lindsay J. Corfield, Thomas A. Heeley, Benjamin Bratby, Ranbir Mannu, Sarah L. Johnson, Victoria Shaw, Holly L. Friett, Louise A. Blakeburn, John S. Kendrick, Michael B. Otteneder. Minipig and Human Metabolism of Aldehyde Oxidase Substrates: In Vitro–In Vivo Comparisons. The AAPS Journal 2017, 19 (4) , 1163-1174. https://doi.org/10.1208/s12248-017-0087-3
    30. Susan Lepri, Martina Ceccarelli, Nicolò Milani, Sara Tortorella, Andrea Cucco, Aurora Valeri, Laura Goracci, Andreas Brink, Gabriele Cruciani. Structure–metabolism relationships in human- AOX: Chemical insights from a large database of aza-aromatic and amide compounds. Proceedings of the National Academy of Sciences 2017, 114 (16) https://doi.org/10.1073/pnas.1618881114
    31. Mohammad-Reza Rashidi, Somaieh Soltani. An overview of aldehyde oxidase: an enzyme of emerging importance in novel drug discovery. Expert Opinion on Drug Discovery 2017, 12 (3) , 305-316. https://doi.org/10.1080/17460441.2017.1284198
    32. Alexander L. Perryman, Thomas P. Stratton, Sean Ekins, Joel S. Freundlich. Predicting Mouse Liver Microsomal Stability with “Pruned” Machine Learning Models and Public Data. Pharmaceutical Research 2016, 33 (2) , 433-449. https://doi.org/10.1007/s11095-015-1800-5
    33. J. Matthew Hutzler, Michael A. Zientek. Non-Cytochrome P450 Enzymes and Glucuronidation. 2015, 79-130. https://doi.org/10.1039/9781782622376-00079
    34. Kanika V. Choughule, Carolyn A. Joswig-Jones, Jeffrey P. Jones. Interspecies differences in the metabolism of methotrexate: An insight into the active site differences between human and rabbit aldehyde oxidase. Biochemical Pharmacology 2015, 96 (3) , 288-295. https://doi.org/10.1016/j.bcp.2015.05.010
    35. Jasleen K. Sodhi, Susan Wong, Donald S. Kirkpatrick, Lichuan Liu, S. Cyrus Khojasteh, Cornelis E. C. A. Hop, John T. Barr, Jeffrey P. Jones, Jason S. Halladay. A Novel Reaction Mediated by Human Aldehyde Oxidase: Amide Hydrolysis of GDC-0834. Drug Metabolism and Disposition 2015, 43 (6) , 908-915. https://doi.org/10.1124/dmd.114.061804
    36. Seigo Sanoh, Yoshitaka Tayama, Kazumi Sugihara, Shigeyuki Kitamura, Shigeru Ohta. Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy. Drug Metabolism and Pharmacokinetics 2015, 30 (1) , 52-63. https://doi.org/10.1016/j.dmpk.2014.10.009
    37. Li Di. The role of drug metabolizing enzymes in clearance. Expert Opinion on Drug Metabolism & Toxicology 2014, 10 (3) , 379-393. https://doi.org/10.1517/17425255.2014.876006
    38. Patrik Rydberg, Flemming Steen Jørgensen, Lars Olsen. Use of density functional theory in drug metabolism studies. Expert Opinion on Drug Metabolism & Toxicology 2014, 10 (2) , 215-227. https://doi.org/10.1517/17425255.2014.864278
    39. Kanika V. Choughule, John T. Barr, Jeffrey P. Jones. Evaluation of Rhesus Monkey and Guinea Pig Hepatic Cytosol Fractions as Models for Human Aldehyde Oxidase. Drug Metabolism and Disposition 2013, 41 (10) , 1852-1858. https://doi.org/10.1124/dmd.113.052985
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