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Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance

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Abstract

Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High-throughput metabolic stability screening has enabled the advancement of compounds with little to no oxidative metabolism. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for non-CYP-mediated metabolism. UGTs, esterases, and aldehyde oxidase are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such pathways including elucidation of major metabolites. To predict human PK parameters for P450-mediated metabolism, in vitro-in vivo extrapolation using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, such methods have not been sufficiently evaluated for non-P450 enzymes. In addition to the involvement of the liver, extrahepatic enzymes (intestine, kidney, lung) are also likely to contribute to these pathways. While there has been considerable progress in predicting metabolic pathways and clearance primarily mediated by the liver, progress in characterizing extrahepatic metabolism and prediction of clearance has been slow. Well-characterized in vitro systems or in vivo animal models to assess drug-drug interaction potential and intersubject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non-CYP-mediated metabolism and to understand the enzymes involved followed by pharmacokinetic studies in the appropriately characterized surrogate species. The review will highlight progress made in establishing in vitro-in vivo correlation, predicting human clearance and avoiding costly clinical failures when non-CYP-mediated metabolic pathways are predominant.

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References

  1. Garattini E, Terao M. Increasing recognition of the importance of aldehyde oxidase in drug development and discovery. Drug Metab Rev. 2011;43(3):374–86. doi:10.3109/03602532.2011.560606.

    Article  CAS  PubMed  Google Scholar 

  2. Terao M, Romao MJ, Leimkuhler S, Bolis M, Fratelli M, Coelho C, et al. Structure and function of mammalian aldehyde oxidases. Arch Toxicol. 2016;90(4):753–80. doi:10.1007/s00204-016-1683-1.

    Article  CAS  PubMed  Google Scholar 

  3. Beedham C. Molybdenum hydroxylases: biological distribution and substrate-inhibitor specificity. Prog Med Chem. 1987;24:85–127.

    Article  CAS  PubMed  Google Scholar 

  4. Kitamura S, Sugihara K, Ohta S. Drug-metabolizing ability of molybdenum hydroxylases. Drug Metab Pharmacokinet. 2006;21(2):83–98.

    Article  CAS  PubMed  Google Scholar 

  5. Sugihara K, Kitamura S, Tatsumi K. Involvement of mammalian liver cytosols and aldehyde oxidase in reductive metabolism of zonisamide. Drug Metab Dispos. 1996;24(2):199–202.

    CAS  PubMed  Google Scholar 

  6. Obach RS, Prakash C, Kamel AM. Reduction and methylation of ziprasidone by glutathione, aldehyde oxidase, and thiol S-methyltransferase in humans: an in vitro study. Xenobiotica. 2012;42(11):1049–57. doi:10.3109/00498254.2012.683203.

    Article  CAS  PubMed  Google Scholar 

  7. Sodhi JK, Wong S, Kirkpatrick DS, Liu L, Khojasteh SC, Hop CE, et al. A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab Dispos. 2015;43(6):908–15. doi:10.1124/dmd.114.061804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Moriwaki Y, Yamamoto T, Takahashi S, Tsutsumi Z, Hada T. Widespread cellular distribution of aldehyde oxidase in human tissues found by immunohistochemistry staining. Histol Histopathol. 2001;16(3):745–53.

    CAS  PubMed  Google Scholar 

  9. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human phase I metabolizing enzymes except for cytochrome P450 and phase II metabolizing enzymes. Drug Metab Pharmacokinet. 2006;21(5):357–74.

    Article  CAS  PubMed  Google Scholar 

  10. Coelho C, Foti A, Hartmann T, Santos-Silva T, Leimkuhler S, Romao MJ. Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase. Nat Chem Biol. 2015;11(10):779–83. doi:10.1038/nchembio.1895.

    Article  CAS  PubMed  Google Scholar 

  11. Dalvie D, Zhang C, Chen W, Smolarek T, Obach RS, Loi CM. Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences. Drug Metab Dispos. 2010;38(4):641–54. doi:10.1124/dmd.109.030783.

    Article  CAS  PubMed  Google Scholar 

  12. Akabane T, Tanaka K, Irie M, Terashita S, Teramura T. Case report of extensive metabolism by aldehyde oxidase in humans: pharmacokinetics and metabolite profile of FK3453 in rats, dogs, and humans. Xenobiotica. 2011;41(5):372–84. doi:10.3109/00498254.2010.549970.

    Article  CAS  PubMed  Google Scholar 

  13. Dittrich C, Greim G, Borner M, Weigang-Kohler K, Huisman H, Amelsberg A, et al. Phase I and pharmacokinetic study of BIBX 1382 BS, an epidermal growth factor receptor (EGFR) inhibitor, given in a continuous daily oral administration. Eur J Cancer. 2002;38(8):1072–80.

    Article  CAS  PubMed  Google Scholar 

  14. Kaye B, Offerman JL, Reid JL, Elliott HL, Hillis WS. A species difference in the presystemic metabolism of carbazeran in dog and man. Xenobiotica. 1984;14(12):935–45. doi:10.3109/00498258409151492.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang X, Liu HH, Weller P, Zheng M, Tao W, Wang J, et al. In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor. Pharmacogenomics J. 2011;11(1):15–24. doi:10.1038/tpj.2010.8.

    Article  CAS  PubMed  Google Scholar 

  16. Diamond S, Boer J, Maduskuie Jr TP, Falahatpisheh N, Li Y, Yeleswaram S. Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications. Drug Metab Dispos. 2010;38(8):1277–85. doi:10.1124/dmd.110.032375.

    Article  CAS  PubMed  Google Scholar 

  17. Strolin Benedetti M, Whomsley R, Baltes E. Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics. Expert Opin Drug Metab Toxicol. 2006;2(6):895–921. doi:10.1517/17425255.2.6.895.

    Article  CAS  PubMed  Google Scholar 

  18. Strelevitz TJ, Orozco CC, Obach RS. Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance. Drug Metab Dispos. 2012;40(7):1441–8. doi:10.1124/dmd.112.045195.

    Article  CAS  PubMed  Google Scholar 

  19. Nirogi R, Kandikere V, Palacharla RC, Bhyrapuneni G, Kanamarlapudi VB, Ponnamaneni RK, et al. Identification of a suitable and selective inhibitor towards aldehyde oxidase catalyzed reactions. Xenobiotica. 2014;44(3):197–204. doi:10.3109/00498254.2013.819594.

    Article  CAS  PubMed  Google Scholar 

  20. Baer BR, Wienkers LC, Rock DA. Time-dependent inactivation of P450 3A4 by raloxifene: identification of Cys239 as the site of apoprotein alkylation. Chem Res Toxicol. 2007;20(6):954–64. doi:10.1021/tx700037e.

    Article  CAS  PubMed  Google Scholar 

  21. Zientek M, Jiang Y, Youdim K, Obach RS. In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos. 2010;38(8):1322–7. doi:10.1124/dmd.110.033555.

    Article  CAS  PubMed  Google Scholar 

  22. Hutzler JM, Yang YS, Albaugh D, Fullenwider CL, Schmenk J, Fisher MB. Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes. Drug Metab Dispos. 2012;40(2):267–75. doi:10.1124/dmd.111.042861.

    Article  CAS  PubMed  Google Scholar 

  23. Akabane T, Gerst N, Naritomi Y, Masters JN, Tamura K. A practical and direct comparison of intrinsic metabolic clearance of several non-CYP enzyme substrates in freshly isolated and cryopreserved hepatocytes. Drug Metab Pharmacokinet. 2012;27(2):181–91.

    Article  CAS  PubMed  Google Scholar 

  24. Zientek MA, Youdim K. Reaction phenotyping: advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes. Drug Metab Dispos. 2015;43(1):163–81. doi:10.1124/dmd.114.058750.

    Article  PubMed  CAS  Google Scholar 

  25. Kitamura S, Sugihara K, Nakatani K, Ohta S, Ohhara T, Ninomiya S, et al. Variation of hepatic methotrexate 7-hydroxylase activity in animals and humans. IUBMB Life. 1999;48(6):607–11. doi:10.1080/713803569.

    Article  CAS  PubMed  Google Scholar 

  26. Al-Salmy HS. Individual variation in hepatic aldehyde oxidase activity. IUBMB Life. 2001;51(4):249–53. doi:10.1080/152165401753311799.

    Article  CAS  PubMed  Google Scholar 

  27. Fu C, Di L, Han X, Soderstrom C, Snyder M, Troutman MD, et al. Aldehyde oxidase 1 (AOX1) in human liver cytosols: quantitative characterization of AOX1 expression level and activity relationship. Drug Metab Dispos. 2013;41(10):1797–804. doi:10.1124/dmd.113.053082.

    Article  CAS  PubMed  Google Scholar 

  28. Hutzler JM, Yang YS, Brown C, Heyward S, Moeller T. Aldehyde oxidase activity in donor-matched fresh and cryopreserved human hepatocytes and assessment of variability in 75 donors. Drug Metab Dispos. 2014;42(6):1090–7. doi:10.1124/dmd.114.057984.

    Article  PubMed  CAS  Google Scholar 

  29. Barr JT, Jones JP, Oberlies NH, Paine MF. Inhibition of human aldehyde oxidase activity by diet-derived constituents: structural influence, enzyme-ligand interactions, and clinical relevance. Drug Metab Dispos. 2015;43(1):34–41. doi:10.1124/dmd.114.061192.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Tayama Y, Sugihara K, Sanoh S, Miyake K, Morita S, Kitamura S, et al. Effect of tea beverages on aldehyde oxidase activity. Drug Metab Pharmacokinet. 2011;26(1):94–101.

    Article  CAS  PubMed  Google Scholar 

  31. Kestell P, Dunlop IC, McCrystal MR, Evans BD, Paxton JW, Gamage RS, et al. Plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial. Cancer Chemother Pharmacol. 1999;44(1):45–50. doi:10.1007/s002800050943.

    Article  CAS  PubMed  Google Scholar 

  32. Akabane T, Gerst N, Masters JN, Tamura K. A quantitative approach to hepatic clearance prediction of metabolism by aldehyde oxidase using custom pooled hepatocytes. Xenobiotica. 2012;42(9):863–71. doi:10.3109/00498254.2012.670736.

    Article  CAS  PubMed  Google Scholar 

  33. Manevski N, Balavenkatraman KK, Bertschi B, Swart P, Walles M, Camenisch G, et al. Aldehyde oxidase activity in fresh human skin. Drug Metab Dispos. 2014;42(12):2049–57. doi:10.1124/dmd.114.060368.

    Article  PubMed  CAS  Google Scholar 

  34. Kurosaki M, Bolis M, Fratelli M, Barzago MM, Pattini L, Perretta G, et al. Structure and evolution of vertebrate aldehyde oxidases: from gene duplication to gene suppression. Cell Mol Life Sci. 2013;70(10):1807–30. doi:10.1007/s00018-012-1229-5.

    Article  CAS  PubMed  Google Scholar 

  35. Beedham C, Bruce SE, Critchley DJ, al-Tayib Y, Rance DJ. Species variation in hepatic aldehyde oxidase activity. Eur J Drug Metab Pharmacokinet. 1987;12(4):307–10.

    Article  CAS  PubMed  Google Scholar 

  36. Garattini E, Terao M. The role of aldehyde oxidase in drug metabolism. Expert Opin Drug Metab Toxicol. 2012;8(4):487–503. doi:10.1517/17425255.2012.663352.

    Article  CAS  PubMed  Google Scholar 

  37. Hutzler JM, Cerny MA, Yang YS, Asher C, Wong D, Frederick K, et al. Cynomolgus monkey as a surrogate for human aldehyde oxidase metabolism of the EGFR inhibitor BIBX1382. Drug Metab Dispos. 2014;42(10):1751–60. doi:10.1124/dmd.114.059030.

    Article  PubMed  CAS  Google Scholar 

  38. Hosea NA, Collard WT, Cole S, Maurer TS, Fang RX, Jones H, et al. Prediction of human pharmacokinetics from preclinical information: comparative accuracy of quantitative prediction approaches. J Clin Pharmacol. 2009;49(5):513–33. doi:10.1177/0091270009333209.

    Article  CAS  PubMed  Google Scholar 

  39. Cashman J, Perroti B, Berkman C, Lin J. Pharmacokinetics and molecular detoxification. Environ Health Perspect. 1996;104:23–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Redinbo MR, Potter PM. Mammalian carboxylesterases: from drug targets to protein therapeutics. Drug Discov Today. 2005;10:313–25.

    Article  CAS  PubMed  Google Scholar 

  41. Laizure SC, Herring V, Hu Z, Witbrodt K, Parker RB. The role of human carboxylesterases in drug metabolism: have we overlooked their importance? Pharmacotherapy. 2013;33(2):210–22. doi:10.1002/phar.1194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hatfield MJ, Tsurkan L, Garrett M, Shaver T, Edwards CC, Hyatt JL, et al. Organ-specific carboxylesterase profiling identifies the small intestine and kidney as major contributors of activation of the anticancer prodrug CPT-11. Biochem Pharmacol. 2011;81:24–31.

    Article  CAS  PubMed  Google Scholar 

  43. Wadkins RM, Morton CL, Weeks JK, Oliver L, Wierdl M, Danks MK, et al. Structural constraints affect the metabolism of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) by carboxylesterases. Mol Pharmacol. 2001;60:355–62.

    CAS  PubMed  Google Scholar 

  44. Bencharit S, Morton CL, Howard-Williams EL, Danks MK, Potter PM, Redinbo MR. Structural insights into CPT-11 activation by mammalian carboxylesterases. Nat Struct Biol. 2002;9:337–42.

    Article  CAS  PubMed  Google Scholar 

  45. Bencharit S, Morton CL, Xue Y, Potter PM, Redinbo MR. Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nat Struct Biol. 2003;10:349–56.

    Article  CAS  PubMed  Google Scholar 

  46. Wierdl M, Tsurkan L, Hyatt JL, Edwards CC, Hatfield MJ, Morton CL, et al. An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11. Cancer Gene Ther. 2008;15(3):183–92. doi:10.1038/sj.cgt.7701112.

    Article  CAS  PubMed  Google Scholar 

  47. Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM, et al. Crystal structure of human carboxylesterase 1 complexed with the Alzheimer’s drug tacrine. From binding promiscuity to selective inhibition. Chem Biol. 2003;10:341–9.

    Article  CAS  PubMed  Google Scholar 

  48. Humerickhouse R, Lohrbach K, Li L, Bosron W, Dolan M. Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2. Cancer Res. 2000;60:1189–92.

    CAS  PubMed  Google Scholar 

  49. Khanna R, Morton CL, Danks MK, Potter PM. Proficient metabolism of CPT-11 by a human intestinal carboxylesterase. Cancer Res. 2000;60:4725–8.

    CAS  PubMed  Google Scholar 

  50. Potter PM, Pawlik CA, Morton CL, Naeve CW, Danks MK. Isolation and partial characterization of a cDNA encoding a rabbit liver carboxylesterase that activates the prodrug irinotecan (CPT-11). Cancer Res. 1998;52:2646–51.

    Google Scholar 

  51. Gilson MK, Straatsma TP, McCammon JA, Ripoll DR, Faerman CH, Axelsen PH, et al. Open “back door” in a molecular dynamics simulation of acetylcholinesterase. Science. 1994;263:1276–8.

    Article  CAS  PubMed  Google Scholar 

  52. Zhou H-X, Wlodek ST, McCammon JA. Conformation gating as a mechanism for enzyme specificity. Proc Natl Acad Sci U S A. 1998;95:9280–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hatfield MJ, Tsurkan L, Hyatt JL, Yu X, Edwards CC, Hicks LD, et al. Biochemical and molecular analysis of carboxylesterase-mediated hydrolysis of cocaine and heroin. Br J Pharmacol. 2010;160(8):1916–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Morton CL, Potter PM. Comparison of Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris, Spodoptera frugiperda and COS7 cells for recombinant gene expression: application to a rabbit liver carboxylesterase. Mol Biotechnol. 2000;16:193–202.

    Article  CAS  PubMed  Google Scholar 

  55. Guemei AA, Cottrell J, Band R, Hehman H, Prudhomme M, Pavlov MV, et al. Human plasma carboxylesterase and butyrylcholinesterase enzyme activity: correlations with SN-38 pharmacokinetics during a prolonged infusion of irinotecan. Cancer Chemother Pharmacol. 2001;47:283–90.

    Article  CAS  PubMed  Google Scholar 

  56. Morton CL, Wadkins RM, Danks MK, Potter PM. The anticancer prodrug CPT-11 is a potent inhibitor of acetylcholinesterase but is rapidly catalyzed to SN-38 by butyrylcholinesterase. Cancer Res. 1999;59(7):1458–63.

    CAS  PubMed  Google Scholar 

  57. Williams ET, Wang H, Wrighton SA, Qian YW, Perkins EJ. Genomic analysis of the carboxylesterases: identification and classification of novel forms. Mol Phylogenet Evol. 2010;57(1):23–34. doi:10.1016/j.ympev.2010.05.018.

    Article  CAS  PubMed  Google Scholar 

  58. Holmes RS, Cox LA, VandeBerg JL. Comparative studies of mammalian acid lipases: evidence for a new gene family in mouse and rat (Lipo). Comp Biochem Physiol Part D Genomics Proteomics. 2010;5(3):217–26. doi:10.1016/j.cbd.2010.05.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Morton CL, Wierdl M, Oliver L, Ma M, Danks MK, Stewart CF, et al. Activation of CPT-11 in mice: identification and analysis of a highly effective plasma esterase. Cancer Res. 2000;60:4206–10.

    CAS  PubMed  Google Scholar 

  60. Danks MK, Morton CL, Krull EJ, Cheshire PJ, Richmond LB, Naeve CW, et al. Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy. Clin Cancer Res. 1999;5:917–24.

    CAS  PubMed  Google Scholar 

  61. Morton CL, Iacono L, Hyatt JL, Taylor KR, Cheshire PJ, Houghton PJ, et al. Metabolism and antitumor activity of CPT-11 in plasma esterase-deficient mice. Cancer Chemother Pharmacol. 2005;56:629–36.

    Article  CAS  PubMed  Google Scholar 

  62. Soares ER. Identification of a new allele of Es-1 segregating in an inbred strain of mice. Biochem Genet. 1979;17(7/8):577–83.

    Article  CAS  PubMed  Google Scholar 

  63. Nishimuta H, Houston JB, Galetin A. 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. 2014;42(9):1522–31. doi:10.1124/dmd.114.057372.

    Article  PubMed  CAS  Google Scholar 

  64. Williams ET, Bacon JA, Bender DM, Lowinger JJ, Guo WK, Ehsani ME, et al. Characterization of the expression and activity of carboxylesterases 1 and 2 from the beagle dog, cynomolgus monkey, and human. Drug Metab Dispos. 2011;39(12):2305–13. doi:10.1124/dmd.111.041335.

    Article  CAS  PubMed  Google Scholar 

  65. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL, et al. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008;82(6):1241–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhu HJ, Wang X, Gawronski BE, Brinda BJ, Angiolillo DJ, Markowitz JS. Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation. J Pharmacol Exp Ther. 2013;344(3):665–72. doi:10.1124/jpet.112.201640.

    Article  CAS  PubMed  Google Scholar 

  67. Zhu HJ, Markowitz JS. Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants. Drug Metab Dispos. 2009;37(2):264–7. doi:10.1124/dmd.108.024943.

    Article  CAS  PubMed  Google Scholar 

  68. Hu ZY, Edginton AN, Laizure SC, Parker RB. Physiologically based pharmacokinetic modeling of impaired carboxylesterase-1 activity: effects on oseltamivir disposition. Clin Pharmacokinet. 2014;53(9):825–36. doi:10.1007/s40262-014-0160-3.

    Article  CAS  PubMed  Google Scholar 

  69. Hatfield MJ, Potter PM. Carboxylesterase inhibitors. Expert Opin Ther Pat. 2011;21(8):1159–71. doi:10.1517/13543776.2011.586339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hicks LD, Hyatt JL, Moak T, Edwards CC, Tsurkan L, Wierdl M, et al. Analysis of the inhibition of mammalian carboxylesterases by novel fluorobenzoins and fluorobenzils. Bioorg Med Chem. 2007;15:3801–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hicks LD, Hyatt JL, Stoddard S, Tsurkan L, Edwards CC, Wadkins RM, et al. Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan; CPT-11) toxicity. J Med Chem. 2009;52(12):3742–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hyatt JL, Moak T, Hatfield JM, Tsurkan L, Edwards CC, Wierdl M, et al. Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. J Med Chem. 2007;50:1876–85.

    Article  CAS  PubMed  Google Scholar 

  73. Hyatt JL, Stacy V, Wadkins RM, Yoon KJ, Wierdl M, Edwards CC, et al. Inhibition of carboxylesterases by benzil (diphenylethane-1,2-dione) and heterocyclic analogues is dependent upon the aromaticity of the ring and the flexibility of the dione moiety. J Med Chem. 2005;48:5543–50.

    Article  CAS  PubMed  Google Scholar 

  74. Hyatt JL, Tsurkan L, Wierdl M, Edwards CC, Danks MK, Potter PM. Intracellular inhibition of carboxylesterases by benzil: modulation of CPT-11 cytotoxicity. Mol Cancer Ther. 2006;5:2281–8.

    Article  CAS  PubMed  Google Scholar 

  75. Hyatt JL, Wadkins RM, Tsurkan L, Hicks LD, Hatfield MJ, Edwards CC, et al. Planarity and constraint of the carbonyl groups in 1,2-diones are determinants for selective inhibition of human carboxylesterase 1. J Med Chem. 2007;50:5727–34.

    Article  CAS  PubMed  Google Scholar 

  76. Parkinson EI, Jason Hatfield M, Tsurkan L, Hyatt JL, Edwards CC, Hicks LD, et al. Requirements for mammalian carboxylesterase inhibition by substituted ethane-1,2-diones. Bioorg Med Chem. 2011;19(15):4635–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wadkins RM, Hyatt JL, Yoon KJ, Morton CL, Lee RE, Damodaran K, et al. Identification of novel selective human intestinal carboxylesterase inhibitors for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis, and biological activity. Mol Pharmacol. 2004;65:1336–43.

    Article  CAS  PubMed  Google Scholar 

  78. Wadkins RM, Hyatt JL, Yoon KJ, Morton CL, Lee RE, Damodaran K, et al. Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis, and biological activity. Mol Pharmacol. 2004;65(6):1336–43. doi:10.1124/mol.65.6.1336.

    Article  CAS  PubMed  Google Scholar 

  79. Young BM, Hyatt JL, Bouck DC, Chen T, Hanumesh P, Price J, et al. Structure-activity relationships of substituted 1-pyridyl-2-phenyl-1,2-ethanediones: potent, selective carboxylesterase inhibitors. J Med Chem. 2010;53(24):8709–15. doi:10.1021/jm101101q.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hatfield MJ, Tsurkan LG, Hyatt JL, Edwards CC, Lemoff A, Jeffries C, et al. Modulation of esterified drug metabolism by tanshinones from Salvia miltiorrhiza (“Danshen”). J Nat Prod. 2013;76(1):36–44. doi:10.1021/np300628a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tsurkan LG, Hatfield MJ, Edwards CC, Hyatt JL, Potter PM. Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors. Chem Biol Interact. 2013;203(1):226–30. doi:10.1016/j.cbi.2012.10.018.

    Article  CAS  PubMed  Google Scholar 

  82. Remmel RP, Nagar S, Argikar UA. Conjugative metabolism of drugs. In: Zhang D, Zhu M, Humphreys WG, editors. Drug metabolism in drug design and development. 1st ed. Hoboken: Wiley-Interscience; 2007. p. 609.

    Google Scholar 

  83. Argikar UA. Unusual glucuronides. Drug Metab Dispos Biol Fate Chem. 2012;40(7):1239–51. doi:10.1124/dmd.112.045096.

    Article  CAS  PubMed  Google Scholar 

  84. Bushee JL, Argikar UA. An experimental approach to enhance precursor ion fragmentation for metabolite identification studies: application of dual collision cells in an orbital trap. Rapid Commun Mass Spectrom. 2011;25(10):1356–62. doi:10.1002/rcm.4996.

    Article  CAS  PubMed  Google Scholar 

  85. Mackenzie PI, Bock KW, Burchell B, Guillemette C, Ikushiro S, Iyanagi T, et al. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics. 2005;15(10):677–85.

    Article  CAS  PubMed  Google Scholar 

  86. Mackenzie PI, Rogers A, Treloar J, Jorgensen BR, Miners JO, Meech R. Identification of UDP glycosyltransferase 3A1 as a UDP N-acetylglucosaminyltransferase. J Biol Chem. 2008;283(52):36205–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Mackenzie PI, Rogers A, Elliot DJ, Chau N, Hulin JA, Miners JO, et al. The novel UDP glycosyltransferase 3a2: cloning, catalytic properties and tissue distribution. Mol Pharmacol. 2011;79(3):472–8.

    Article  CAS  PubMed  Google Scholar 

  88. Fallon JK, Neubert H, Goosen TC, Smith PC. Targeted precise quantification of 12 human recombinant uridine-diphosphate glucuronosyl transferase 1A and 2B isoforms using nano-ultra-high-performance liquid chromatography/tandem mass spectrometry with selected reaction monitoring. Drug Metab Dispos. 2013;41(12):2076–80. doi:10.1124/dmd.113.053801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Remmel RP, Zhou J, Argikar UA. UDP-glucuronosyl transferases. In: Rodrigues DA, editor. Drug-drug interactions. 2nd ed. New York: Informa Health Care; 2008. p. 744.

    Google Scholar 

  90. Argikar UA, Liang G, Bushee JL, Hosagrahara VP, Lee W. Evaluation of pharmaceutical excipients as cosolvents in 4-methyl umbelliferone glucuronidation in human liver microsomes: applications for compounds with low solubility. Drug Metab Pharmacokinetics. 2011;26(1):102–6.

    Article  CAS  Google Scholar 

  91. Miners JO, Smith PA, Sorich MJ, McKinnon RA, Mackenzie PI. Predicting human drug glucuronidation parameters: application of in vitro and in silico modeling approaches. Annu Rev Pharmacol Toxicol. 2004;44:1–25. doi:10.1146/annurev.pharmtox.44.101802.121546.

    Article  CAS  PubMed  Google Scholar 

  92. Walsky RL, Bauman JN, Bourcier K, Giddens G, Lapham K, Negahban A, et al. Optimized assays for human UDP-glucuronosyltransferase (UGT) activities: altered alamethicin concentration and utility to screen for UGT inhibitors. Drug Metab Dispos. 2012;40(5):1051–65. doi:10.1124/dmd.111.043117.

    Article  CAS  PubMed  Google Scholar 

  93. Engtrakul JJ, Foti RS, Strelevitz TJ, Fisher MB. Altered AZT (3′-azido-3′-deoxythymidine) glucuronidation kinetics in liver microsomes as an explanation for underprediction of in vivo clearance: comparison to hepatocytes and effect of incubation environment. Drug Metab Dispos. 2005;33(11):1621–7. doi:10.1124/dmd.105.005058.

    Article  CAS  PubMed  Google Scholar 

  94. Gunduz M, Argikar UA, Baeschlin D, Ferreira S, Hosagrahara V, Harriman S. Identification of a novel N-carbamoyl glucuronide: in vitro, in vivo, and mechanistic studies. Drug Metab Dispos Biol Fate Chem. 2010;38(3):361–7. doi:10.1124/dmd.109.030650.

    Article  CAS  PubMed  Google Scholar 

  95. Fisher MB, Campanale K, Ackermann BL, VandenBranden M, Wrighton SA. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos. 2000;28(5):560–6.

    CAS  PubMed  Google Scholar 

  96. Soars MG, Ring BJ, Wrighton SA. The effect of incubation conditions on the enzyme kinetics of UDP-glucuronosyltransferases. Drug Metab Dispos. 2003;31(6):762–7.

    Article  CAS  PubMed  Google Scholar 

  97. Uchaipichat V, Mackenzie PI, Guo XH, Gardner-Stephen D, Galetin A, Houston JB, et al. Human UDP-glucuronosyltransferases: isoform selectivity and kinetics of 4-methylumbelliferone and 1-naphthol glucuronidation, effects of organic solvents, and inhibition by diclofenac and probenecid. Drug Metab Dispos. 2004;32(4):413–23. doi:10.1124/dmd.32.4.413.

    Article  CAS  PubMed  Google Scholar 

  98. Chauret N, Gauthier A, Nicoll-Griffith DA. Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes. Drug Metab Dispos. 1998;26(1):1–4.

    CAS  PubMed  Google Scholar 

  99. Oleson L, Court MH. Effect of the beta-glucuronidase inhibitor saccharolactone on glucuronidation by human tissue microsomes and recombinant UDP-glucuronosyltransferases. J Pharm Pharmacol. 2008;60(9):1175–82. doi:10.1211/jpp.60.9.0009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Remmel RP, Zhou J, Argikar UA. Uridine diphospho glucuronosyl transferases. In: Pearson P, Wienkers L, editors. Handbook of drug metabolism. 2nd ed. New York: Informa Health Care; 2009. p. 630.

    Google Scholar 

  101. Gill KL, Houston JB, Galetin A. Characterization of in vitro glucuronidation clearance of a range of drugs in human kidney microsomes: comparison with liver and intestinal glucuronidation and impact of albumin. Drug Metab Dispos. 2012;40(4):825–35. doi:10.1124/dmd.111.043984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rowland A, Gaganis P, Elliot DJ, Mackenzie PI, Knights KM, Miners JO. Binding of inhibitory fatty acids is responsible for the enhancement of UDP-glucuronosyltransferase 2B7 activity by albumin: implications for in vitro-in vivo extrapolation. J Pharmacol Exp Ther. 2007;321(1):137–47.

    Article  CAS  PubMed  Google Scholar 

  103. Rowland A, Knights KM, Mackenzie PI, Miners JO. The “albumin effect” and drug glucuronidation: bovine serum albumin and fatty acid-free human serum albumin enhance the glucuronidation of UDP-glucuronosyltransferase (UGT) 1A9 substrates but not UGT1A1 and UGT1A6 activities. Drug Metab Dispos. 2008;36(6):1056–62. doi:10.1124/dmd.108.021105.

    Article  CAS  PubMed  Google Scholar 

  104. Bushee JL, Liang G, Dunne CE, Harriman SP, Argikar UA. Identification of saturated and unsaturated fatty acids released during microsomal incubations. Xenobiotica Fate Foreign Compd Biol Syst. 2014;44(8):687–95. doi:10.3109/00498254.2014.884253.

    Article  CAS  Google Scholar 

  105. Lombardo F, Waters NJ, Argikar UA, Dennehy MK, Zhan J, Gunduz M, et al. Comprehensive assessment of human pharmacokinetic prediction based on in vivo animal pharmacokinetic data, part 1: volume of distribution at steady state. J Clin Pharmacol. 2013;53(2):167–77. doi:10.1177/0091270012440281.

    Article  CAS  PubMed  Google Scholar 

  106. Lombardo F, Waters NJ, Argikar UA, Dennehy MK, Zhan J, Gunduz M, et al. Comprehensive assessment of human pharmacokinetic prediction based on in vivo animal pharmacokinetic data, part 2: clearance. J Clin Pharmacol. 2013;53(2):178–91. doi:10.1177/0091270012440282.

    Article  CAS  PubMed  Google Scholar 

  107. Deguchi T, Watanabe N, Kurihara A, Igeta K, Ikenaga H, Fusegawa K, et al. Human pharmacokinetic prediction of UDP-glucuronosyltransferase substrates with an animal scale-up approach. Drug Metab Dispos. 2011;39(5):820–9. doi:10.1124/dmd.110.037457.

    Article  CAS  PubMed  Google Scholar 

  108. Gibson CR, Lu P, Maciolek C, Wudarski C, Barter Z, Rowland-Yeo K, et al. Using human recombinant UDP-glucuronosyltransferase isoforms and a relative activity factor approach to model total body clearance of laropiprant (MK-0524) in humans. Xenobiotica. 2013;43(12):1027–36. doi:10.3109/00498254.2013.791761.

    Article  CAS  PubMed  Google Scholar 

  109. Cubitt HE, Houston JB, Galetin A. Relative importance of intestinal and hepatic glucuronidation—impact on the prediction of drug clearance. Pharm Res. 2009;26(5):1073–83. doi:10.1007/s11095-008-9823-9.

    Article  CAS  PubMed  Google Scholar 

  110. Cubitt HE, Houston JB, Galetin A. Prediction of human drug clearance by multiple metabolic pathways: integration of hepatic and intestinal microsomal and cytosolic data. Drug Metab Dispos. 2011;39(5):864–73. doi:10.1124/dmd.110.036566.

    Article  CAS  PubMed  Google Scholar 

  111. Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos. 2009;37(1):82–9. doi:10.1124/dmd.108.023853.

    Article  CAS  PubMed  Google Scholar 

  112. Zhou J, Argikar UA, Remmel RP. Functional analysis of UGT1A4(P24T) and UGT1A4(L48V) variant enzymes. Pharmacogenomics. 2011;12(12):1671–9. doi:10.2217/pgs.11.105.

    Article  CAS  PubMed  Google Scholar 

  113. Krishnaswamy S, Hao Q, Al-Rohaimi A, Hesse LM, von Moltke LL, Greenblatt DJ, et al. UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: II. Functional impact of the three most common nonsynonymous UGT1A6 polymorphisms (S7A, T181A, and R184S). J Pharmacol Exp Ther. 2005;313(3):1340–6. doi:10.1124/jpet.104.081968.

    Article  CAS  PubMed  Google Scholar 

  114. Miners JO, Knights KM, Houston JB, Mackenzie PI. In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Biochem Pharmacol. 2006;71(11):1531–9. doi:10.1016/j.bcp.2005.12.019.

    Article  CAS  PubMed  Google Scholar 

  115. Boase S, Miners JO. In vitro-in vivo correlations for drugs eliminated by glucuronidation: investigations with the model substrate zidovudine. Br J Clin Pharmacol. 2002;54(5):493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mistry M, Houston JB. Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab Dispos. 1987;15(5):710–7.

    CAS  PubMed  Google Scholar 

  117. Soars MG, Burchell B, Riley RJ. In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharmacol Exp Ther. 2002;301(1):382–90.

    Article  CAS  PubMed  Google Scholar 

  118. Naritomi Y, Nakamori F, Furukawa T, Tabata K. Prediction of hepatic and intestinal glucuronidation using in vitro-in vivo extrapolation. Drug Metab Pharmacokinet. 2015;30(1):21–9. doi:10.1016/j.dmpk.2014.10.001.

    Article  CAS  PubMed  Google Scholar 

  119. Galetin A. Rationalizing underprediction of drug clearance from enzyme and transporter kinetic data: from in vitro tools to mechanistic modeling. Methods Mol Biol. 2014;1113:255–88. doi:10.1007/978-1-62703-758-7_13.

    Article  CAS  PubMed  Google Scholar 

  120. Fujiwara R, Nakajima M, Yamanaka H, Katoh M, Yokoi T. Product inhibition of UDP-glucuronosyltransferase (UGT) enzymes by UDP obfuscates the inhibitory effects of UGT substrates. Drug Metab Dispos. 2008;36(2):361–7. doi:10.1124/dmd.107.018705.

    Article  CAS  PubMed  Google Scholar 

  121. Manevski N, Yli-Kauhaluoma J, Finel M. UDP-glucuronic acid binds first and the aglycone substrate binds second to form a ternary complex in UGT1A9-catalyzed reactions, in both the presence and absence of bovine serum albumin. Drug Metab Dispos. 2012;40(11):2192–203. doi:10.1124/dmd.112.047746.

    Article  CAS  PubMed  Google Scholar 

  122. Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201–8. doi:10.1124/dmd.104.000794.

    Article  CAS  PubMed  Google Scholar 

  123. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, et al. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab Dispos. 2006;34(1):191–7. doi:10.1124/dmd.105.007633.

    Article  CAS  PubMed  Google Scholar 

  124. Tornio A, Filppula AM, Kailari O, Neuvonen M, Nyronen TH, Tapaninen T, et al. Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions. Clin Pharmacol Ther. 2014;96(4):498–507. doi:10.1038/clpt.2014.141.

    Article  CAS  PubMed  Google Scholar 

  125. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther. 2004;311(1):228–36. doi:10.1124/jpet.104.068536.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Sincere thanks to Jennifer L. (Bushee) Dumouchel, Mithat Gunduz, Amanda Cirello, and Bindi Sohal for critical discussions. Work in the Potter lab is supported in part by NIH grants CA108775 and AT007531, a Cancer Center Core grant CA21765, and the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital (SJCRH).

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Authors and Affiliations

  1. Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts, USA

    Upendra A. Argikar

  2. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

    Philip M. Potter

  3. Q2 Solutions, Bioanalytical and ADME Labs, Indianapolis, Indiana, USA

    J. Matthew Hutzler

  4. Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Punit H. Marathe

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  1. Upendra A. Argikar
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Correspondence to Punit H. Marathe.

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Argikar, U.A., Potter, P.M., Hutzler, J.M. et al. 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, 1391–1405 (2016). https://doi.org/10.1208/s12248-016-9962-6

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