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Review Articles

Recent developments in predicting CYP-independent metabolism

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Pages 188-206 | Received 22 Apr 2021, Accepted 23 Apr 2021, Published online: 25 May 2021

References

  • Abbasi A, Joswig-Jones CA, Jones JP. 2020. Site-directed mutagenesis at the molybdenum pterin cofactor site of the human aldehyde oxidase: interrogating the kinetic differences between human and cynomolgus monkey. Drug Metab Dispos. 48(12):1364–1371.
  • Abbasi A, Paragas EM, Joswig-Jones CA, Rodgers JT, Jones JP. 2019. Time course of aldehyde oxidase and why it is nonlinear. Drug Metab Dispos. 47(5):473–483.
  • Ahire DS, Basit A, Krasu M, Prasad B. 2021. Ultrasensitive quantification of drug-metabolizing enzymes and transporters in small sample volume by microflow LC-MS/MS. J Pharm Sci. DOI:10.1016/j.xphs.2021.03.020.
  • Akabane T, Tanaka K, Irie M, Terashita S, Teramura T. 2011. Case report of extensive metabolism by aldehyde oxidase in humans: pharmacokinetics and metabolite profile of FK3453 in rats, dogs, and humans. Xenobiotica. 41(5):372–384.
  • Alfaro JF, Jones JP. 2008. Studies on the mechanism of aldehyde oxidase and xanthine oxidase. J Org Chem. 73(23):9469–9472.
  • Allocati N, Masulli M, Di IC, Federici L. 2018. Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis . 7(1):8.
  • Argikar UA, Potter PM, Hutzler JM, Marathe PH. 2016. Challenges and opportunities with non-CYP enzymes aldehyde oxidase, carboxylesterase, and UDP-glucuronosyltransferase: focus on reaction phenotyping and prediction of human clearance. Aaps J. 18(6):1391–1405.
  • Awasthi YC, Sharma R, Singhal SS. 1994. Human glutathione S-transferases. Int J Biochem. 26(3):295–308.
  • Balke K, Kadow M, Mallin H, Sass S, Bornscheuer UT. 2012. Discovery, application and protein engineering of Baeyer-Villiger monooxygenases for organic synthesis. Org Biomol Chem. 10(31):6249–6265.
  • Banoglu E. 2000. Current status of the cytosolic sulfotransferases in the metabolic activation of promutagens and procarcinogens. CDM. 1(1):1–30.
  • Barr JT, Choughule KV, Nepal S, Wong T, Chaudhry AS, Joswig-Jones CA, Zientek M, Strom SC, Schuetz EG, Thummel EK, et al. 2014. Why do most human liver cytosol preparations lack xanthine oxidase activity? Drug Metab Dispos. 42(4):695–699.
  • Basit A, Neradugomma NK, Wolford C, Fan PW, Murray B, Takahashi RH, Khojasteh SC, Smith BJ, Heyward S, Totah RA, et al. 2020. Characterization of differential tissue abundance of major non-CYP enzymes in human. Mol Pharm. 17(11):4114–4124.
  • Battelli MG, Polito L, Bortolotti M, Bolognesi A. 2016. Xanthine oxidoreductase in drug metabolism: beyond a role as detoxifying enzyme. Curr Med Chem. 23(35):4027–4036.
  • Beedham C, Bruce SE, Critchley DJ, Al-Tayib y, Rance DJ. 1987. Species variation in hepatic aldehyde oxidase activity. Eur J Drug Metab Pharmacokinet. 12(4):307–310.
  • Benet LZ, Bowman CM, Koleske ML, Rinaldi CL, Sodhi JK. 2019a. Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs. J Pharmacokinet Pharmacodyn. 46(2):155–163.
  • Benet LZ, Bowman CM, Sodhi JK. 2019b. How transporters have changed basic pharmacokinetic understanding. Aaps J. 21(6):103.
  • Benet LZ, Sodhi JK. 2020. Investigating the theoretical basis for in vitro-in vivo extrapolation (IVIVE) in predicting drug metabolic clearance and proposing future experimental pathways. Aaps J. 22(5):120.
  • Bhatt DK, Gaedigk A, Pearce RE, Leeder JS, Prasad B. 2017. Age-dependent protein abundance of cytosolic alcohol and aldehyde dehydrogenases in human liver. Drug Metab Dispos. 45(9):1044–1048.
  • Bhatt DK, Prasad B. 2018. Critical issues and optimized practices in quantification of protein abundance level to determine interindividual variability in DMET proteins by LC-MS/MS proteomics. Clin Pharmacol Ther. 103(4):619–630.
  • Borges F, Fernandes E, Roleira F. 2002. Progress towards the discovery of xanthine oxidase inhibitors. Curr Med Chem. 9(2):195–217.
  • Bowers GD, Tenero D, Patel P, Huynh P, Sigafoos J, O'Mara K, Young GC, Dumont E, Cunningham E, Kurtinecz M, et al. 2013. Disposition and metabolism of GSK2251052 in humans: a novel boron-containing antibiotic. Drug Metab Dispos. 41(5):1070–1081.
  • Bredemeier M, Lopes LM, Eisenreich MA, Hickmann S, Bongiorno GK, d’Avila R, Morsch ALB, Stein FS, Campos GGD. 2018. Xanthine oxidase inhibitors for prevention of cardiovascular events: a systemic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 18(1):24.
  • Brent J. 2009. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 360(21):2216–2223.
  • Cashman JR. 2005. Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Biochem Biophys Res Commun. 338(1):559–604.
  • Cashman JR, Gohdes M, de Kater A, Schoenhard G. 2020. N-oxygenation of oxycodone and retro-reduction of oxycodone N-oxide. Drug Metab Dispos. 48(2):106–115.
  • Cashman JR, Zhang J. 2006. Human flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol. 46:65–100.
  • Cerny MA. 2016. Prevalence of non-cytochrome P450-mediated metabolism in Food and Drug Administration-approved oral and intravenous drugs: 2006-2015. Drug Metab Dispos. 44(8):1246–1252.
  • Chen C-H, Ferreira JCB, Gross ER, Mochly-Rosen D. 2014. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev. 94(1):1–34.
  • Cheong J, Halladay JS, Plise E, Sodhi JK, Salphati L. 2017. The effects of drug metabolizing enzyme inhibitors on hepatic efflux and uptake transporters. Drug Metab Lett. 11(2):111–118.
  • Cheshmazar N, Dastmalchi S, Terao M, Garattini E, Hamzeh-Mivehroud M. 2019. Aldehyde oxidase at the crossroad of metabolism and preclinical screening. Drug Metab Rev. 51(4):428–452.
  • Chiba M, Ishii Y, Sugiyama Y. 2009. Prediction of hepatic clearance in human from in vitro data for successful drug development. Aaps J. 11(2):262–276.
  • Coelho C, Foti A, Hartmann T, Santos-Silva T, Leimkühler S, Romão MJ. 2015. Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase. Nat Chem Biol. 11(10):779–783.
  • Coughtrie MWH. 2016. Function and organization of the human cytosolic sulfotransferase (SULT) family. Chem Biol Interact. 259(Pt A):2–7.
  • Couto N, Al-Majdoub ZM, Gibson S, Davies PJ, Achour B, Harwood MD, Carlson G, Barber J, Rostami-Hodjegan A, Warhurst G. 2020. Quantitative proteomics of clinically relevant drug-metabolizing enzymes and drug transporters and their intercorrelations in the human small intestine. Drug Metab Dispos. 48(4):245–254.
  • Cronin CN, Liu JH, Grable N, Strelevitz TJ, Obach RS, Carlo A. 2021. Production of active recombinant human aldehyde oxidase (AOX) in the baculovirus expression vector system (BEVS) and deployment in a pre-clinical fraction-of-control AOX compound exposure assay. Protein Expr Purif. 177:105749.
  • Crouch RD, Blobaum AL, Felts AS, Conn PJ, Lindsley CW. 2017. Species-specific involvement of aldehyde oxidase and xanthine oxidase in the metabolism of the Pyrimidine-Containing mGlu5-Negative Allosteric Modulator VU0424238 (Auglurant). Drug Metab Dispos. 45(12):1245–1259.
  • Crouch RD, Hutzler JM, Daniels JS. 2018. A novel in vitro allometric scaling methodology for aldehyde oxidase substrates to enable selection of appropriate species for traditional allometry. Xenobiotica. 48(3):219–231.
  • Crouch RD, Morrison RD, Byers FW, Lindsley CW, Emmitte KA, Daniels JS. 2016. Evaluating the disposition of a mixed aldehyde oxidase/cytochrome P450 substrate in rats with attenuated P450 activity. Drug Metab Dispos. 44(8):1296–1303.
  • Cruciani G, Milani N, Benedetti P, Lepri S, Cesarini L, Baroni M, Spyrakis F, Tortorella S, Mosconi E, Goracci L. 2018. From experiments to a fast easy-to-use computational methodology to predict human aldehyde oxidase selectivity and metabolic reactions. J Med Chem. 61(1):360–371.
  • Dalvie D, Di L. 2019. Aldehyde oxidase and its role as a drug metabolizing enzyme. Pharmacol Ther. 201:137–180.
  • De Sousa Mendes M, Orton AL, Humphries HE, Jones B, Gardner I, Neuhoff S, Reddy VP. 2020. A laboratory-specific scaling factor to predict the in vivo human clearance of aldehyde oxidase substrates. Drug Metab Dispos. 48(11):1231–1238.
  • DeLeve LD, Wang X. 2000. Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology. 60(3):143–154.
  • Deshwal S, Di Sante M, Di Lisa F, Kaludercic N. 2017. Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease. Curr Opin Pharmacol. 33:64–69.
  • Di L. 2014. The role of drug metabolizing enzymes in clearance. Expert Opin Drug Metab Toxicol. 10(3):379–393.
  • Di L. 2019. The impact of carboxylesterases in drug metabolism and pharmacokinetics. Curr Drug Metab. 20(2):91–102.
  • Di L, Balesano A, Jordan S, Shi SM. 2021. The role of alcohol dehydrogenase in drug metabolism: beyond ethanol oxidation. AAPS J. 23(1):20.
  • Diamond S, Boer J, Maduskuie TP, Jr Falahatpisheh N, Li Y, Yeleswaram S. 2010. Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications. Drug Metab Dispos. 38(8):1277–1285.
  • Diao X, Pang X, Xie C, Guo Z, Zhong D, Chen X. 2014. Bioactivation of 3-n-butylphthalide via sulfation of its major metabolite 3-hydroxy-NBP: mediated mainly by sulfotransferase 1A1. Drug Metab Dispos. 42(4):774–781.
  • Dick RA. 2018. Refinement of in vitro methods for identification of aldehyde oxidase substrates reveals metabolites of kinase inhibitors. Drug Metab Dispos. 46(6):846–859.
  • Docci L, Klammers F, Ekiciler A, Molitor B, Umehara K, Walter I, Krähenbühl S, Parrott N, Fowler S. 2020b. In vitro to in vivo extrapolation of metabolic clearance for UGT substrates using short-term suspension and long-term co-cultured human hepatocytes. AAPS J. 22(6):131.
  • Docci L, Umehara K, Krähenbühl S, Fowler S, Parrott N. 2020a. Construction and verification of physiologically based pharmacokinetic models for four drugs majorly cleared by glucuronidation: lorazepam, oxazepam, naloxone, and zidovudine. AAPS J. 22(6):128.
  • Doerksen MJ, Jones RS, Coughtrie MWH, Collier AC. 2021. Parameterization of microsomal and cytosolic scaling factors: methodological and biological considerations for scalar derivation and validation. Eur J Drug Metab Pharmacokinet. 46(2):173–183.
  • Dong D, Ako R, Hu M, Wu B. 2012. Understanding substrate selectivity of human UDP-glucuronosyltransferases through QSAR modeling and analysis of homologous enzymes. Xenobiotica. 42(8):808–820.
  • Dong GQ, Calhoun S, Fan H, Kalyanaraman C, Branch MC, Mashiyama ST, London N, Jacobson MP, Babbitt PC, Shoichet BK, et al. 2014. Prediction of substrates for glutathione transferases by covalent docking. J Chem Inf Model. 54(6):1687–1699.
  • Driscoll JP, Aliagas I, Harris JJ, Halladay JS, Khatib-Shahidi S, Deese A, Segraves N, Khojasteh-Bakht SC. 2010. Formation of a quinoneimine intermediate of 4-fluoro-N-methylaniline by FMO1: carbon oxidation plus defluorination. Chem Res Toxicol. 23(5):861–863.
  • Driscoll JP, Sadlowski CM, Shah NR, Feula A. 2020. Metabolism and bioactivation: It's Time to Expect the Unexpected. J Med Chem. 63(12):6303–6314.
  • Dunn RT, 2nd, Klaassen CD. 1998. Tissue-specific expression of rat sulfotransferase messenger RNAs. Drug Metab Dispos. 26(6):598–604.
  • Dupree EJ, Jayathirtha M, Yorkey H, Mihasan M, Petre BA, Darie CC. 2020. A critical review of bottom-up proteomics: the good, the bad, and the future of this field. Proteomes. 8(3):14.
  • El-Khateeb E, Achour B, Scotcher D, Al-Majdoub ZM, Athwal V, Barber J, Rostami-Hodjegan A. 2020. Scaling factors for clearance in adult liver cirrhosis. Drug Metab Dispos. 48(12):1271–1282.
  • Emoto C, Murase S, Sawada Y, Jones BC, Iwasaki K. 2003. In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: a comparison with SKF-525A and ketoconazole. Drug Metab Pharmacokinet. 18(5):287–295.
  • Fiorentini F, Geier M, Binda C, Winkler M, Faber K, Hall M, Mattevi A. 2016. Biocatalytic charachterization of human FMO5: unearthing Baeyer-Villiger reactions in humans. ACS Chem Biol. 11(4):1039–1048.
  • Fiorentini F, Romero E, Fraaije MW, Faber K, Hall M, Mattevi A. 2017. Baeyer-Villiger Monooxygenase FMO5 as Entry Point in Drug Metabolism. ACS Chem Biol. 12(9):2379–2387.
  • Fisher MB, Campanale K, Ackermann BL, VandenBranden M, Wrighton SA. 2000. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos. 28(5):560–566.
  • Foti RS, Dalvie DK. 2016. Cytochrome P450 and non-cytochrome P450 oxidative metabolism: contributions to the pharmacokinetics, safety, and efficacy of xenobiotics. Drug Metab Dispos. 44(8):1229–1245.
  • Foti RS, Wahlstrom JL. 2008. CYP2C19 inhibition: the impact of substrate probe selection on in vitro inhibition profiles. Drug Metab Dispos. 36(3):523–528.
  • Fujiwara R, Yoda E, Tukey RH. 2018. Species differences in drug glucuronidation: humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans. Drug Metab Pharmacokinet. 33(1):9–16.
  • Fürst MJLJ, Gran-Scheuch A, Aalbers FS, Fraaije MW. 2019. Bayers-Villiger monooxygenases: tunable oxidative biocatalysts. ACS Catal. 9(12):11207–11241.
  • Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, McManus ME. 2006. Human sulfotransferases and their role in chemical metabolism. Toxicol Sci. 90(1):5–22.
  • Garattini E, Fratelli M, Terao M. 2009. The mammalian aldehyde oxidase gene family. Hum Genomics. 4(2):119–130.
  • Garattini E, Terao M. 2012. The role of aldehyde oxidase in drug metabolism. Expert Opin Drug Metab Toxicol. 8(4):487–503.
  • Gaweska H, Fitzpatrick PF. 2011. Structures and mechanism of the monoamine oxidase family. Biomol Concepts. 2(5):365–377.
  • Ge S, Tu Y, Hu M. 2016. Challenges and opportunities with predicting in vivo phase II metabolism via glucuronidation from in vitro data. Curr Pharmacol Rep. 2(6):326–338.
  • Ge S, Wei Y, Yin T, Xu B, Gao S, Hu M. 2017. Transport-glucuronidation classification system and PBPK modeling: new approach to predict the impact of transporters on disposition of glucuronides. Mol Pharm. 14(9):2884–2898.
  • Glatt H. 2000. Sulfotransferases in the bioactivation of xenobiotics. Chem Biol Interact. 129(1-2):141–170.
  • Gröer C, Busch D, Patrzyk M, Beyer K, Busemann A, Heidecke CD, Drozdzik M, Siegmund W, Oswald S. 2014. Absolute protein quantification of clinically relevant cytochrome P450 enzymes and UDP-glucuronosyltransferases by mass spectrometry-based targeted proteomics. J Pharm Biomed Anal. 100:393–401.
  • Higgins P, Dawson J, Lees KR, McArthur K, Quinn TJ, Walters MR. 2012. Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. Cardiovasc Ther. 30(4):217–226.
  • Hille R, Nishino T. 1995. Flavoprotein structure and mechanism. 4. Xanthine oxidase and xanthine dehydrogenase. Faseb J. 9(11):995–1003.
  • Hutzler JM, Yang Y-S, Brown C, Heyward S, Moeller T. 2014. Aldehyde oxidase activity in donor-matched fresh and cryopreserved human hepatocytes and assessment of variability in 75 donors. Drug Metab Dispos. 42(6):1090–1097.
  • Imai T, Ohura K. 2010. The role of intestinal carboxylesterase in the oral absorption of prodrugs. Curr Drug Metab. 11(9):793–805.
  • Jancova P, Anzenbacher P, Anzenbacherova E. 2010. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 154(2):103–116.
  • Jensen KG, Jacobsen A-M, Bundgaard C, Nilausen DØ, Thale Z, Chandrasena G, Jørgensen M. 2017. Lack of exposure in a first-in-man study due to aldehyde oxidase metabolism: investigated by use of 14C-microdose, humanized mice, monkey pharmacokinetics, and in vitro methods. Drug Metab Dispos. 45(1):68–75.
  • Jones BC, Srivastava A, Colclough N, Wilson J, Reddy VP, Amberntsson S, Li D. 2017. An investigation into the prediction of in vivo clearance for a range of flavin-containing monooxygenase substrates. Drug Metab Dispos. 45(10):1060–1067.
  • Kabeya T, Matsumura W, Iwao T, Hosokawa M, Matsunaga T. 2017. Functional analysis of carboxylesterase in human induced pluripotent stem cell-derived enterocytes. Biochem Biophys Res Commun. 486(1):143–148.
  • Kalgutkar AS, Dalvie DK, Castagnoli N, Jr, Taylor TJ. 2001. Interactions of nitrogen-containing xenobiotics with monoamine oxidase (MAO) isozymes A and B: SAR studies on MAO substrates and inhibitors. Chem Res Toxicol. 14(9):1139–1162.
  • Kamel A, Colizza K, Gunduz M, Harriman S, Obach RS. 2012. In vitro-in vivo correlation for intrinsic clearance for CP-409,092 and sumatriptan: a case study to predict the in vivo clearance for compounds metabolized by monoamine oxidase. Xenobiotica. 42(4):355–362.
  • Kiang TKL, Ensom MHH, Chang TKH. 2005. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 106(1):97–132.
  • Klinenberg JR, Goldfinger SE, Seegmiller JE. 1965. The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout. Ann Intern Med. 62:639–647.
  • Knights KM, Spencer SM, Fallon JK, Chau N, Smith PC, Miners JO. 2016. Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and xenobiotic glucuronidation clearance. Br J Clin Pharmacol. 81(6):1153–1164.
  • Krueger SK, Williams DE. 2005. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther. 106(3):357–387.
  • Ladumor MK, Bhatt DK, Gaedigk A, Sharma S, Thakur A, Pearce RE, Leeder JS, Bolger MB, Singh S, Prasad B. 2019. Ontogeny of hepatic sulfotransferases and prediction of age-dependent fractional contribution of sulfation in acetaminophen metabolism. Drug Metab Dispos. 47(8):818–831.
  • Lai WG, Farah N, Moniz GA, Wong YN. 2011. A Bayer-Villiger oxidation specifically catalyzed by human flavin-containing monooxygenase 5. Drug Metab Dispos. 39(1):61–70.
  • Laizure SC, Herring V, Hu Z, Witbrodt K, Parker RB. 2013. The role of human carboxylesterases in drug metabolism: have we overlooked their importance? Pharmacotherapy. 33(2):210–222.
  • Lepri S, Ceccarelli M, Milani N, Tortorella S, Cucco A, Valeri A, Goracci L, Brink A, Cruciani G. 2017. Structure-metabolism relationships in human-AOX: Chemical insights from a large database of aza-aromatic and amide compounds . Proc Natl Acad Sci U S A. 114(16):E3178–E3187.
  • Leung L, Yang X, Strelevitz TJ, Montgomery J, Brown MF, Zientek MA, Banfield C, Gilbert AM, Thorarensen A, Dowty ME. 2017. Clearance prediction of targeted covalent inhibitors by in vitro-in vivo extrapolation of hepatic and extrahepatic clearance mechanisms. Drug Metab Dispos. 45(1):1–7.
  • Li AC, Cui D, Yu E, Dobson K, Hellriegel ET, Robertson P. 2019a. Identification and human exposure prediction of two aldehyde oxidase-mediated metabolites of a methylquinoline-containing drug candidate. Xenobiotica. 49(3):302–312.
  • Li J, Zhu H-J. 2020. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics of drug-metabolizing enzymes and transporters. Molecules. 25(11):2718.
  • Li X-Q, Grönberg G, Bangur E-H, Hayes MA, Castagnoli N, Jr, Weidolf L. 2019b. Metabolism of strained rings: glutathione S-transferase-catalyzed formation of a glutathione-conjugated spiro-azetidine without prior bioactivation. Drug Metab Dispos. 47(11):1247–1256.
  • Li Z, Zhang Y, Gao Y, Xiang Y, Zhang W, Lu C, Zhuang X. 2019c. Atipamezole is a promising non-discriminative inhibitor against pan-CYP450 including diclofenac 4'-hydroxylation: A comparison with ABT for drug ADME optimization and mechanism study. Eur J Pharm Sci. 130:156–165.
  • Linder CD, Renaud NA, Hutzler JM. 2009. Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab Dispos. 37(1):10–13.
  • López-Muñoz F, Alamo C, Juckel G, Assion H-J. 2007. Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors. J Clin Psychopharmacol. 27(6):555–559.
  • Luna G, Dolzhenko AV, Mancera RL. 2019. Inhibitors of xanthine oxidase: scaffold diversity and structure-based drug design. ChemMedChem. 14(7):714–743.
  • Ma Y, Fu Y, Khojasteh SC, Dalvie D, Zhang D. 2017. Glucuronides as potential anionic substrates of human cytochrome P450 2C8 (CYP2C8). J Med Chem. 60(21):8691–8705.
  • Maekawa K, Adachi M, Matsuzawa Y, Zhang Q, Kuroki R, Saito Y, Shah MB. 2017. Structural basis of single-nucleotide polymorphisms in cytochrome P450 2C9. Biochemistry. 56(41):5476–5480.
  • Malik N, Dhiman P, Khatkar A. 2017. In-silico design and ADMET studies of natural compounds as inhibitors of xanthine oxidase (XO) enzyme. Curr Drug Metab. 18(6):577–593.
  • Manevski N, King L, Pitt WR, Lecomte F, Toselli F. 2019. Metabolism by aldehyde oxidase: drug design and complementary approaches to challenges in drug discovery. J Med Chem. 62(24):10955–10994.
  • Masuo Y, Nagamori S, Hasegawa A, Hayashi K, Isozumi N, Nakamichi N, Kanai Y, Kato Y. 2017. Utilization of liver microsomes to estimate hepatic intrinsic clearance of monoamine oxidase substrate drugs in humans. Pharm Res. 34(6):1233–1243.
  • Matsumoto K, Hasegawa T, Ohara K, Kamei T, Koyanagi J, Akimoto M. 2021. Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer-Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid in vitro. Xenobiotica. 51(2):155–166.
  • Matsumoto K, Hasegawa T, Ohara K, Takei C, Kamei T, Koyanagi J, Takahashi T, Akimoto M. 2020. A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) by non-cytochrome P450 enzymes. Xenobiotica. 50(7):783–792.
  • Mizuno Y, Hattori N, Kondo T, Nomoto M, Origasa H, Takahashi R, Yamamoto M, Yanagisawa N. 2017. A randomized double-blind placebo-controlled phase III trial of selegiline monotherapy for early Parkinson disease. Clin Neuropharmacol. 40(5):201–207.
  • Mohos V, Pánovics A, Fliszár-Nyúl E, Schilli G, Hetényi C, Mladěnka P, Needs PW, Kroon PA, Pethő G, Poór M. 2019. Inhibitor effects of quercetin and its human and microbial metabolites on xanthine oxidase enzyme. IJMS. 20(11):2681.
  • Montefiori M, Jørgensen FS, Olsen L. 2017. Aldehyde oxidase: reaction mechanism and prediction of site of metabolism. ACS Omega. 2(8):4237–4244.
  • Montefiori M, Lyngholm-Kjaerby C, Long A, Olsen L, Jørgensen FS. 2019. Fast methods for prediction of aldehyde oxidase-mediated site-of-metabolism. Comput Struct Biotechnol J. 17:345–351.
  • Moore KA, Ramcharitar V, Levine B, Fowler D. 2003. Tentative identification of novel oxycodone metabolites in human urine. J Anal Toxicol. 27(6):346–352.
  • Myers AL, Kawedia JD, Champlin RE, Kramer MA, Nieto Y, Ghose R, Andersson BS. 2017. Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review. Expert Opin Drug Metab Toxicol. 13(9):901–923.
  • Nakamori F, Naritomi Y, Furutani M, Takamura F, Miura H, Murai H, Terashita S, Teramura T. 2011. Correlation of intrinsic in vitro and in vivo clearance for drugs metabolized by hepatic UDP-glucuronosyltransferases in rats. Drug Metab Pharmacokinet. 26(5):465–473.
  • Napoli JL. 1999. Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim Biophys Acta. 1440(2-3):139–162.
  • Naritomi Y, Nakamori F, Furukawa T, Tabata K. 2015. Prediction of hepatic and intestinal glucuronidation using in vitro-in vivo extrapolation. Drug Metab Pharmacokinet. 30(1):21–29.
  • Nawaz MZ, Ain Q, Zahid S, Zulfiqar T, Attique SA, Bilal M. 2020. Physicochemical features and structural analysis of xanthine oxidase as a potential therapeutic target to prevent gout. J Radiat Res Appl Sc. 13(1):616–628.
  • Nishimuta H, Houston JB, Galetin A. 2014. Hepatic, intestinal, renal, and plasma hydrolysis of prodrugs in human, cynomolgus monkey, dog, and rat: implications for in vitro-in vivo extrapolation of clearance of prodrugs. Drug Metab Dispos. 42(9):1522–1531.
  • Nishimuta H, Watanabe T, Bando K. 2019. 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. Aaps J. 21(2):20.
  • Oakley A. 2011. Glutathione transferases: a structural perspective. Drug Metab Rev. 43(2):138–151.
  • Obrezanova O, Segall MD. 2010. Gaussian processes for classification: QSAR modeling of ADMET and target activity. J Chem Inf Model. 50(6):1053–1061.
  • Oda S, Fukami T, Yokoi T, Nakajima M. 2015. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet. 30(1):30–51.
  • Öeren M, Walton PJ, Hunt PA, Ponting DJ, Segall MD. 2021. Predicting reactivity to drug metabolism: beyond P450s-modelling FMOs and UGTs . J Comput Aided Mol Des. 35(4):541–555.
  • Ortiz de Montellano PR. 2018. 1-Aminobenzotriazole: a mechanism-based cytochrome P450 inhibitor and probe of cytochrome P450 biology. Med Chem (Los Angeles). 8(3):038.
  • Ortiz de Montellano PR, Mathews JM. 1981. Autocatalytic alkylation of the cytochrome P-450 prosthetic haem group by 1-aminobenzotriazole. Isolation of an NN-bridged benzyne-protoporphyrin IX adduct. Biochem J. 195(3):761–764.
  • Padmanabhan S, Kaur H, Rao A, Saxena A, Gupta YK, Mariappan TT, Holenarsipur VK. 2019. Effect of pretreatment regimens of 1-aminobenzotriazole on metabolism and gastric emptying of probe compounds in rat. Xenobiotica. 49(6):646–654.
  • Palacharla RC, Molgara P, Panthangi HR, Boggavarapu RK, Manoharan AK, Ponnamaneni RK, Ajjala DR, Nirogi R. 2019. Methoxsalen as an in vitro phenotyping tool in comparison with 1-aminobenzotriazole. Xenobiotica. 49(2):169–176.
  • Păunescu E, Soudani M, Martin P, Scopelliti R, Lo Bello M, Dyson PJ. 2017. Organometallic glutathione S-transferase inhibitors. Organometallics. 36(17):3313–3321.
  • Pelkonen O, Hakkola J, Hukkanen J, Turpeinen M. 2020. CYP-associated drug-drug interactions: a mission accomplished? Arch Toxicol. 94(11):3931–3934.
  • Petersen EN. 1992. The pharmacology and toxicology of disulfiram and its metabolites. Acta Psychiatr Scand Suppl. 369:7–13.
  • Phillips IR, Shephard EA. 2017. Drug metabolism by flavin-containing monooxygenases of human and mouse. Expert Opin Drug Metab Toxicol. 13(2):167–181.
  • Pljesa-Ercegovac M, Savic-Radojevic A, Matic M, Coric V, Djukic T, Radic T, Simic T. 2018. Glutathione transferases: potential targets to overcome chemoresisitance in solid tumors. IJMS. 19(12):3785.
  • Prasad B, Vrana M, Mehrotra A, Johnson K, Bhatt DK. 2017. The promises of quantitative proteomics in precision medicine. J Pharm Sci. 106(3):738–744.
  • Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran D-C. 2010. Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J Med Chem. 53(24):8441–8460.
  • Radominska-Pandya A, Bratton SM, Redinbo MR, Miley MJ. 2010. The crystal structure of human UDP-glucuronosyltransferase 2B7 C-terminal end is the first mammalian UGT target to be revealed: the significance for human UGTs from both the 1A and 2B families. Drug Metab Rev. 42(1):133–144.
  • Radominska-Pandya A, Czernik PJ, Little JM, Battaglia E, Mackenzie PI. 1999. Structural and functional studies of UDP-glucuronosyltransferases. Drug Metab Rev. 31(4):817–899.
  • Rashidi M-R, Soltani S. 2017. An overview of aldehyde oxidase: an enzyme of emerging importance in novel drug discovery. Expert Opin Drug Discov. 12(3):305–316.
  • Rautio J, Meanwell NA, Di L, Hageman MJ. 2018. The expanding role of prodrugs in contemporary drug design and development. Nat Rev Drug Discov. 17(8):559–587.
  • Riches Z, Stanley EL, Bloomer JC, Coughtrie MWH. 2009. Quantitative evaluation of the expression and activity of five major sulfotransferases (SULTs) in human tissues: the SULT “pie. Drug Metab Dispos. 37(11):2255–2261.
  • Romański M, Główka FK. 2019. In vitro study of the enzymatic and nonenzymatic conjugation of treosulfan with glutathione. Eur J Drug Metab Pharmacokinet. 44(5):653–657.
  • Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA. 1991. Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry. 30(13):3247–3255.
  • Rowland A, Miners JO, Mackenzie PI. 2013. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol. 45(6):1121–1132.
  • Russel LE, and Schleiff MA, Gonzalez E, Bart AG, Broccatelli F, Hartman J, Humphreys WG, Lauschke VM, Iain M, Prasad B, Scott EE, et al. 2020. Advances in the study of drug metabolism - symposium report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX). ).Drug Metab Rev. 52(3):395–407.
  • Ruzza P, Calderan A. 2013. Glutathione transferase (GST)-activated prodrugs. Pharmaceutics. 5(2):220–231.
  • Sahi J, Khan KK, Black CB. 2008. Aldehyde oxidase activity and inhibition in hepatocytes and cytosolic fractions from mouse, rat, monkey and human. Drug Metab Lett. 2(3):176–183.
  • Sane RS, Ramsden D, Sabo JP, Cooper C, Rowland L, Ting N, Whitcher-Johnstone A, Tweedie DJ. 2016. Contribution of major metabolites towards complex drug-drug interactions of deleobuvir: in vitro predictions and in vivo outcomes. Drug Metab Dispos. 44(3):466–475.
  • Saravanakumar A, Sadighi A, Ryu R, Akhlaghi F. 2019. Physicochemical properties, biotransformation, and transport pathways of established and newly approved medications: a systematic review of the top 200 most prescribed drugs vs. the FDA-approved drugs between 2005 and 2016. Clin Pharmacokinet. 58(10):1281–1294.
  • Sato D, Kisen T, Kumagai M, Ohta K. 2018. Synthesis, structure-activity relationships, and mechanistic studies of 5-arylazo-tropolone derivatives as novel xanthine oxidase (XO) inhibitors. Bioorg Med Chem. 26(2):536–542.
  • Schleiff MA, Sodhi JK. 2021. International Society for the Study of Xenobiotics (ISSX) New Investigator Group Committee 2019–2020 concluding remarks. Drug Metab Rev. DOI:10.1080/03602532.2021.1910293
  • Shah P, Siramshetty VB, Zakharov AV, Southall NT, Xu X, Nguyen D-T. 2020. Predicting liver cytosol stability of small molecules. J Cheminform. 12(1):21.
  • Shaik AN, LeDuc BW, Khan AA. 2017. Characterization of 1-aminobenzotriazole and ketoconazole as novel inhibitors of monoamine oxidase (MAO): an in vitro investigation. Eur J Drug Metab Pharmacokinet. 42(5):827–834.
  • Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, Thompson DC, Vasiliou V. 2013. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med. 56:89–101.
  • Sodhi JK, Benet LZ. 2020. The necessity of using changes in absorption time to implicate intestinal transporter involvement in oral drug-drug interactions. Aaps J. 22(5):111.
  • Sodhi JK, Benet LZ. 2021. Successful and unsuccessful prediction of human hepatic clearance for lead optimization. J Med Chem. 64(7):3546–3559.
  • Sodhi JK, Ford KA, Mukadam S, Wong S, Hop CECA, Khojasteh SC, Halladay JS. 2014. 1-Aminobenzotriazole coincubated with (S)-warfarin results in potent inactivation of CYP2C9. Drug Metab Dispos. 42(5):813–817.
  • Sodhi JK, Wong S, Kirkpatrick DS, Liu L, Khojasteh SC, Hop CECA, Barr JT, Jones JP, Halladay JS. 2015. A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab Dispos. 43(6):908–915.
  • Strange RC, Spiteri MA, Ramachandran S, Fryer AA. 2001. Glutathione-S-transferase family of enzymes. Mutat Res. 482(1-2):21–26.
  • Stringer RA, Weber E, Tigani B, Lavan P, Medhurst S, Sohal B. 2014. 1-Aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats. Drug Metab Dispos. 42(7):1117–1124.
  • Subbaiah MAM, Mandlekar S, Desikan S, Ramar T, Subramani L, Annadurai M, Desai SD, Sinha S, Jenkins SM, Krystal MR, Subramanian M, et al. 2019. Design, synthesis, and pharmacokinetic evaluation of phosphate and amino acid ester prodrugs for improving the oral bioavailability of the HIV-1 protease inhibitor atazanavir. J Med Chem. 62(7):3553–3574.
  • Sutanto F, Konstantinidou M, Dömling A. 2020. Covalent inhibitors: a rational approach to drug discovery. RSC Med Chem. 11(8):876–884.
  • Tang M, Mukundan M, Yang J, Charpentier N, LeCluyse EL, Black C, Yang D, Shi D, Yan B. 2006. Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J Pharmacol Exp Ther. 319(3):1467–1476.
  • Tao W, Zhao D, Sun M, Wang Z, Lin B, Bao Y, Li Y, He Z, Sun Y, Sun J. 2018. Intestinal absorption and activation of decitabine amino acid ester prodrugs mediated by peptide transporter PEPT1 and enterocyte enzymes. Drug Metab Dispos. 42(9):1522–1531.
  • Thase ME, Trivedi MH, Rush AJ. 1995. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology. 12(3):185–219.
  • Thomas T. 2000. Monoamine oxidase-B inhibitors in the treatment of Alzheimer’s disease. Neurobiol Aging. 21(2):343–348.
  • Tornio A, Filppula AM, Niemi M, Backman JT. 2019. Clinical studies on drug-drug interactions involving metabolism and transport: methodology, pitfalls, and interpretation. Clin Pharmacol Ther. 105(6):1345–1361.
  • Townsend DM, Tew KD. 2003. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene. 22(47):7369–7375.
  • Trapa PE, Beaumont K, Atkinson K, Eng H, King-Ahmad A, Scott DO, Maurer TS, Di L. 2017. In Vitro-In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein-Cannulated Monkey . J Pharm Sci. 106(3):898–905.
  • U.S. Food and Drug Administration, Center for Drug Evaluation and Research 2020. In vitro drug interaction studies – cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry. Silver Spring, MD, USA.
  • Uehara S, Yoneda N, Higuchi Y, Yamazaki H, Suemizu H. 2020. Human aldehyde oxidase 1-mediated carbazeran oxidation in chimeric TK-NOG mice transplanted with human hepatocytes. Drug Metab Dispos. 48(7):580–586.
  • Umehara K-I, Zollinger M, Kigondu E, Witschi M, Juif C, Huth F, Schiller H, Chibale K, Camenisch G. 2016. Esterase phenotyping in human liver in vitro: specificity of carboxylesterase inhibitors. Xenobiotica. 46(10):862–867.
  • Uno Y, Murayama N, Yamazaki H. 2019. Molecular and functional characterization of cytosolic sulfotransferases in cynomolgus macaque. Biochem Pharmacol. 166:153–162.
  • Uno Y, Uehara S, Murayama N, Shimizu M, Yamazaki H. 2020. Expression of functional sulfotransferases (SULT) 1A1, 1A3, 1B1, 1C2, 1E1, and 2A1 in common marmosets. Biochem Pharmacol. 180:114189.
  • Urabe H, Miyakoshi N, Ohtake N, Nozoe A, Ochi M, Fukasawa M, Kinoshita K, Yamaguchi J-I, Marumo T, Hikichi H, et al. 2020. Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability. Eur J Med Chem. 203:112521.
  • Verma N, Kumar P, Mitra S, Taneja S, Dhooria S, Das A, Duseja A, Dhiman RK, Chawla Y. 2018. Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini-review of the literature. Hepatol Commun. 2(2):142–147.
  • Wang D, Zou L, Jin Q, Hou J, Ge G, Yang L. 2018. Human carboxylesterases: a comprehensive review. Acta Pharm Sin B. 8(5):699–712.
  • Wells PG, Mackenzie PI, Chowdhury JR, Guillemette C, Gregory PA, Shii Y, Hansen AJ, Kessler FK, Kim PM, Chowdhury NR, et al. 2004. Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos. 32(3):281–290.
  • Wilkinson DJ, Southall RL, Li M, Wright LM, Corfield LJ, Heeley TA, Bratby B, Mannu R, Johnson SL, Shaw V, Friett HL, et al. 2017. Minipig and human metabolism of aldehyde oxidase substrates: in vitro-in vivo Comparisons. Aaps J. 19(4):1163–1174.
  • Williams ET, Bacon JA, Bender DM, Lowinger JJ, Guo W-K, Ehsani ME, Wang X, Wang H, Qian Y-W, Ruterbories KJ, et al. 2011. Characterization of the expression and activity of carboxylesterases 1 and 2 from the beagle dog, cynomolgus monkey, and human. Drug Metab Dispos. 39(12):2305–2313.
  • Williams PA, Cosme J, Ward A, Angove HC, Vinković DM, Jhoti H. 2003. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature. 424(6947):464–468.
  • Wood FL, Houston JB, Hallifax D. 2017. Clearance prediction methodology needs fundamental improvement: trends common to rat and human hepatocytes/microsomes and implications for experimental methodology. Drug Metab Dispos. 45(11):1178–1188.
  • Xu H, Li C, Mozziconacci O, Zhu R, Xu Y, Tang Y, Chen R, Huang Y, Holzbeierlein JM, Schöneich C, et al. 2019. Xanthine oxidase-mediated oxidative stress promotes cancer cell-specific apoptosis. Free Radic Biol Med. 139:70–79.
  • Xu M, Saxena N, Vrana M, Zhang H, Kumar V, Billington S, Khojasteh C, Heyward S, Unadkat JD, Prasad B. 2018. Targeted LC-MS/MS proteomics-based strategy to characterize in vitro models used in drug metabolism and transport studies. Anal Chem. 90(20):11873–11882.
  • Xu Y, Li L, Wang Y, Xing J, Zhou L, Zhong D, Luo X, Jiang H, Chen K, Zheng M, et al. 2017. Aldehyde oxidase mediated metabolism in drug-like molecules: a combined computational and experimental study. J Med Chem. 60(7):2973–2982.
  • Yang X, Johnson N, Di L. 2019. Evaluation of cytochrome P450 selectivity for hydralazine as an aldehyde oxidase inhibitor for reaction phenotyping. J Pharm Sci. 108(4):1627–1630.
  • Yeung AWK, Georgieva MG, Atanasov AG, Tzvetkov NK. 2019. Monoamine oxidases (MAOs) as privileged molecular targets in neuroscience: research literature analysis. Front Mol Neurosci. 12:143.
  • Zhang D, Yang T, Lin J. 2019. A novel xanthine oxidase inhibitor WSJ-557 study on pharmacokinetics and tissue distribution in rats by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 1113:77–83.
  • Zhang H, Wolford C, Basit A, Li AP, Fan PW, Murray BP, Takahashi RH, Khojasteh SC, Smith BJ, Thummel KE, et al. 2020. Regional proteomic quantification of clinically relevant non-cytochrome P450 enzymes along the human small intestine. Drug Metab Dispos. 48(7):528–536.
  • Zhang X, Liu H-H, Weller P, Zheng M, Tao W, Wang J, Liao G, Monshouwer M, Peltz G. 2011. In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor. Pharmacogenomics J. 11(1):15–24.
  • Zhao J, Cui R, Wang L, Chen Y, Fu Z, Ding X, Cui C, Yang T, Li X, Xu Y, et al. 2020. Revisiting aldehyde oxidase mediated metabolism in drug-like molecules: an improved computational model. J Med Chem. 63(12):6523–6537.
  • Zhou S, Li W, Tian M, Zhang N, Yang X, Li W, Peng Y, Zheng J. 2020. Metabolic activation of pirfenidone mediated by cytochrome P450s and sulfotransferases. J Med Chem. 63(15):8059–8068.

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