Reaction phenotyping: Advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes

Drug Metabolism and Disposition

Volumn 43, Issue 1, 2015, Pages 163-181

  Zientek, Michael A ^a   Youdim, Kuresh ^b  

^a PFIZER INC   (United States)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ACYLTRANSFERASE; ALDEHYDE OXIDASE; AMIDASE; AMIDE; AMINE OXIDASE (FLAVIN CONTAINING); AZAMULIN; CYTOCHROME P450; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DRUG METABOLIZING ENZYME; EPOXIDE HYDROLASE; ESTERASE; FLAVIN MONOOXYGENASE; GLUCURONOSYLTRANSFERASE; GLUTATHIONE TRANSFERASE; KETOREDUCTASE; METHYLTRANSFERASE; MIFEPRISTONE; MOLYBDENUM; OSI 930; OXIDOREDUCTASE; PEROXIDASE; PYRROLE DERIVATIVE; RALOXIFENE; SR 9186; SULFOTRANSFERASE; TACROLIMUS; UNCLASSIFIED DRUG; UNINDEXED DRUG; UNSPECIFIC MONOOXYGENASE; UREA DERIVATIVE; DRUG;

AEROBIC METABOLISM; DRUG CLEARANCE; DRUG CONJUGATION; DRUG ELIMINATION; DRUG HYDROLYSIS; DRUG METABOLISM; DRUG STRUCTURE; ENZYME INHIBITION; ENZYME SUBSTRATE; HUMAN; IN VITRO STUDY; PHARMACOKINETICS; PHENOTYPE; PREDICTION; REVIEW; DRUG DEVELOPMENT; DRUG INTERACTION; METABOLISM; PHYSIOLOGY; PROCEDURES;

ALDEHYDE OXIDASE; CYTOCHROME P-450 ENZYME SYSTEM; DRUG DISCOVERY; DRUG INTERACTIONS; GLUCURONOSYLTRANSFERASE; HUMANS; PHARMACEUTICAL PREPARATIONS;

EID: 84919667116     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.114.058750     Document Type: Review

References (153)

1. Achour B, Russell MR, Barber J, and Rostami-Hodjegan A (2014) Simultaneous quantification of the abundance of several cytochrome P450 and uridine 59-diphospho-glucuronosyltransferase enzymes in human liver microsomes using multiplexed targeted proteomics. Drug Metab Dispos 42:500-510.
2. Ahlström MM, Ridderström M, and Zamora I (2007) CYP2C9 structure-metabolism relationships: substrates, inhibitors, and metabolites. J Med Chem 50:5382-5391.
3. Akabane T, Gerst N, Masters JN, and Tamura K (2012) A quantitative approach to hepatic clearance prediction of metabolism by aldehyde oxidase using custom pooled hepatocytes. Xenobiotica 42:863-871.
4. Alfaro JF, Joswig-Jones CA, Ouyang W, Nichols J, Crouch GJ, and Jones JP (2009) Purification and mechanism of human aldehyde oxidase expressed in Escherichia coli. Drug Metab Dispos 37:2393-2398.
5. Alonen A, Finel M, and Kostiainen R (2008) The human UDP-glucuronosyltransferase UGT1A3 is highly selective towards N2 in the tetrazole ring of losartan, candesartan, and zolarsartan. Biochem Pharmacol 76:763-772.
6. Al-Salmy HS (2001) Individual variation in hepatic aldehyde oxidase activity. IUBMB Life 51: 249-253.
7. Barr JT, Jones JP, Joswig-Jones CA, and Rock DA (2013) Absolute quantification of aldehyde oxidase protein in human liver using liquid chromatography-tandem mass spectrometry. Mol Pharm 10:3842-3849.
8. Barry A and Levine M (2010) A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients. Ther Drug Monit 32: 708-714.
9. Basu NK, Kovarova M, Garza A, Kubota S, Saha T, Mitra PS, Banerjee R, Rivera J, and Owens IS (2005) Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity. Proc Natl Acad Sci USA 102:6285-6290.
10. Bauman JN, Goosen TC, Tugnait M, Peterkin V, Hurst SI, Menning LC, Milad M, Court MH, and Williams JA (2005) Udp-glucuronosyltransferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes. Drug Metab Dispos 33:1349-1354.
11. Boase S and Miners JO (2002) In vitro-in vivo correlations for drugs eliminated by glucuronidation: investigations with the model substrate zidovudine. Br J Clin Pharmacol 54:493-503.
12. Burk O, Tegude H, Koch I, Hustert E, Wolbold R, Glaeser H, Klein K, Fromm MF, Nuessler AK, and Neuhaus P, et al. (2002) Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 277:24280-24288.
13. Chauret N, Gauthier A, and Nicoll-Griffith DA (1998) Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes. Drug Metab Dispos 26:1-4.
14. Chen Y, Liu L, Nguyen K, and Fretland AJ (2011) Utility of intersystem extrapolation factors in early reaction phenotyping and the quantitative extrapolation of human liver microsomal intrinsic clearance using recombinant cytochromes P450. Drug Metab Dispos 39:373-382.
15. Choughule KV, Barr JT, and Jones JP (2013) Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase. Drug Metab Dispos 41: 1852-1858.
16. Chouinard S, Tessier M, Vernouillet G, Gauthier S, Labrie F, Barbier O, and Bélanger A (2006) Inactivation of the pure antiestrogen fulvestrant and other synthetic estrogen molecules by UDPglucuronosyltransferase1A enzymes expressed in breast tissue. Mol Pharmacol 69:908-920.
17. Court MH (2004) In vitro identification of UDP-glucuronosyl-transferases (UGTs) involved in drug metabolism, in Optimization in Drug Discovery (Yan Z and Caldwell GW eds) pp 185-202, Humana Press Inc., Totowa, NJ.
18. Court MH (2005) Isoform-selective probe substrates for in vitro studies of human UDPglucuronosyltransferases. Methods Enzymol 400 : 104-116.
19. Court MH, Duan SX, Guillemette C, Journault K, Krishnaswamy S, Von Moltke LL, and Greenblatt DJ (2002) Stereoselective conjugation of oxazepam by human UDPglucuronosyltransferases (UGTs): S-oxazepam is glucuronidated by UGT2B15, while R-oxazepam is glucuronidated by UGT2B7 and UGT1A9. Drug Metab Dispos 30: 1257-1265.
20. Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, and Greenblatt DJ (2003) Evaluation of 3′-azido-3′-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B72 polymorphism. Drug Metab Dispos 31:1125-1133.
21. Crespi CL (1995) Xenobiotic-metabolizing human cells as tools for pharmacological and toxicological research, in Advances in Drug Research (Meyer UA and Testa B eds) pp 179-235, Academic Press, New York.
22. Crewe HK, Barter ZE, Yeo KR, and Rostami-Hodjegan A (2011) Are there differences in the catalytic activity per unit enzyme of recombinantly expressed and human liver microsomal cytochrome P450 2C9? A systematic investigation into inter-system extrapolation factors. Biopharm Drug Dispos 32:303-318.
23. Dalvie D, Kang P, Zientek M, Xiang C, Zhou S, and Obach RS (2008) Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats. Chem Res Toxicol 21:2260-2271.
24. Daly AK (2006) Significance of the minor cytochrome P450 3A isoforms. Clin Pharmacokinet 45:13-31.
25. Danielson PB (2002) The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 3:561-597.
26. Dennison JB, Jones DR, Renbarger JL, and Hall SD (2007) Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther 321:553-563.
27. Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, and Hall SD (2006) Selective metabolism of vincristine in vitro by CYP3A5. Drug Metab Dispos 34:1317-1327.
28. Dennison JB, Mohutsky MA, Barbuch RJ, Wrighton SA, and Hall SD (2008) Apparent high CYP3A5 expression is required for significant metabolism of vincristine by human cryopreserved hepatocytes. J Pharmacol Exp Ther 327:248-257.
29. Dickins M, Galetin A, and Proctor N(2007) Modelling and simulation of pharmacokinetic aspects of cytochrome P450-based metabolic drug-drug interactions, in Comprehensive Medicinal Chemistry II (Taylor JB and Triggle DJ eds) pp 827-846, Elsevier Ltd., Oxford.
30. Easterbrook J, Lu C, Sakai Y, and Li AP (2001) Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes. Drug Metab Dispos 29:141-144.
31. Emoto C, Murayama N, Rostami-Hodjegan A, and Yamazaki H (2010) Methodologies for investigating drug metabolism at the early drug discovery stage: prediction of hepatic drug clearance and P450 contribution. Curr Drug Metab 11:678-685.
32. Engtrakul JJ, Foti RS, Strelevitz TJ, and Fisher MB (2005) Altered AZT (3 9 -azido-39-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 33:1621-1627.
33. Fallon JK, Harbourt DE, Maleki SH, Kessler FK, Ritter JK, and Smith PC (2008) Absolute quantification of human uridine-diphosphate glucuronosyl transferase (UGT) enzyme isoforms1A1 and 1A6 by tandem LC-MS. Drug Metab Lett 2:210-222.
34. Fallon JK, Neubert H, Goosen T, and Smith PC (2013) Targeted precise quantification of 12 human recombinant UGT1As and 2Bs using NanoUPLC MS/MS with selected reaction monitoring. Drug Metab Dispos 41:2076-2080.
35. Fisher MB, Paine MF, Strelevitz TJ, and Wrighton SA (2001) The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab Rev 33:273-297.
36. Flora DR and Tracy TS (2012) Development of an in vitro system with human liver microsomes for phenotyping of CYP2C9 genetic polymorphisms with a mechanism-based inactivator. Drug Metab Dispos 40:836-842.
37. Floreani M and Carpenedo F (1990) Inhibition of rat liver monooxygenase activities by 2-methyl-1,4-naphthoquinone (menadione). Toxicol Appl Pharmacol 105:333-339.
38. Fu C, Di L, Han X, Soderstrom C, Snyder M, Troutman MD, Obach RS, and Zhang H (2013) Aldehyde oxidase 1 (AOX1) in human liver cytosols: quantitative characterization of AOX1 expression level and activity relationship. Drug Metab Dispos 41:1797-1804.
39. Gaganis P, Miners JO, and Knights KM (2007) Glucuronidation of fenamates: kinetic studies using human kidney cortical microsomes and recombinant UDP-glucuronosyltransferase (UGT) 1A9 and 2B7. Biochem Pharmacol 73:1683-1691.
40. Galetin A, Brown C, Hallifax D, Ito K, and Houston JB (2004) Utility of recombinant enzyme kinetics in prediction of human clearance: impact of variability, CYP3A5, and CYP2C19 on CYP3A4 probe substrates. Drug Metab Dispos 32:1411-1420.
41. Garattini E and Terao M (2013) Aldehyde oxidase and its importance in novel drug discovery: present and future challenges. Expert Opin Drug Discov 8:641-654.
42. Gibson CR, Lu P, Maciolek C, Wudarski C, Barter Z, Rowland-Yeo K, Stroh M, Lai E, and Nicoll-Griffith DA (2013) Using human recombinant UDP-glucuronosyltransferase isoforms and a relative activity factor approach to model total body clearance of laropiprant (MK-0524) in humans. Xenobiotica 43:1027-1036.
43. Gill KL, Houston JB, and Galetin A (2012) 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 40:825-835.
44. Green MD, Bishop WP, and Tephly TR (1995) Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides. Drug Metab Dispos 23:299-302.
45. Harbourt DE, Fallon JK, Ito S, Baba T, Ritter JK, Glish GL, and Smith PC (2012) Quantification of human uridine-diphosphate glucuronosyl transferase 1A isoforms in liver, intestine, and kidney using nanobore liquid chromatography-tandem mass spectrometry. Anal Chem 84: 98-105.
46. Harper TW and Brassil PJ (2008) Reaction phenotyping: current industry efforts to identify enzymes responsible for metabolizing drug candidates. AAPS J 10:200-207.
47. Hartmann T, Terao M, Garattini E, Teutloff C, Alfaro JF, Jones JP, and Leimkühler S (2012) The impact of single nucleotide polymorphisms on human aldehyde oxidase. Drug Metab Dispos 40:856-864.
48. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, Weimar W, and van Gelder T (2003) Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 74:245-254.
49. Huang W, Lin YS, McConn DJ, 2nd, Calamia JC, Totah RA, Isoherranen N, Glodowski M, and Thummel KE (2004) Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos 32:1434-1445.
50. Hutzler JM, Balogh LM, Zientek M, Kumar V, and Tracy TS (2009) Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection. Drug Metab Dispos 37:59-65.
51. Hutzler JM, Yang YS, Albaugh D, Fullenwider CL, Schmenk J, and Fisher MB (2012) Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes. Drug Metab Dispos 40:267-275.
52. Hutzler JM, Yang YS, Brown C, Heyward S, and Moeller T (2014) Aldehyde oxidase activity in donor-matched fresh and cryopreserved human hepatocytes and assessment of variability in 75 donors. Drug Metab Dispos 42:1090-1097.
53. Itäaho K, Court MH, Uutela P, Kostiainen R, Radominska-Pandya A, and Finel M (2009) Dopamine is a low-affinity and high-specificity substrate for the human UDP-glucuronosyltransferase1A10. Drug Metab Dispos 37:768-775.
54. Itäaho K, Mackenzie PI, Ikushiro S, Miners JO, and Finel M (2008) The configuration of the 17-hydroxy group variably influences the glucuronidation of beta-estradiol and epiestradiol by human UDP-glucuronosyltransferases. Drug Metab Dispos 36:2307-2315.
55. Ito K and Houston JB (2005) Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res 22:103-112.
56. Ito M, Yamamoto K, Sato H, Fujiyama Y, and Bamba T (2001) Inhibitory effect of troglitazone on glucuronidation catalyzed by human uridine diphosphate-glucuronosyltransferase 1A6. Eur J Clin Pharmacol 56:893-895.
57. Iwasaki K (2007) Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab Pharmacokinet 22:328-335.
58. Jin Y, Wang YH, Miao J, Li L, Kovacs RJ, Marunde R, Hamman MA, Philips S, Hilligoss J, and Hall SD (2007) Cytochrome P450 3A5 genotype is associated with verapamil response in healthy subjects. Clin Pharmacol Ther 82:579-585.
59. Johns DG (1967) Human liver aldehyde oxidase: differential inhibition of oxidation of charged and uncharged substrates. J Clin Invest 46:1492-1505.
60. Kaivosaari S, Toivonen P, Aitio O, Sipilä J, Koskinen M, Salonen JS, and Finel M (2008) Regioand stereospecific N-glucuronidation of medetomidine: the differences between UDP glucuronosyltransferase (UGT) 1A4 and UGT2B10 account for the complex kinetics of human liver microsomes. Drug Metab Dispos 36:1529-1537.
61. Kasai N, Sakaki T, Shinkyo R, Ikushiro S, Iyanagi T, Ohta M, and Inouye K (2005) Metabolism of 26,26,26,27,27,27-F6-1 alpha,23S,25-trihydroxyvitamin D3 by human UDP-glucuronosyltransferase1A3. Drug Metab Dispos 33:102-107.
62. Kato Y, Nakajima M, Oda S, Fukami T, and Yokoi T (2012) Human UDP-glucuronosyltransferase isoforms involved in haloperidol glucuronidation and quantitative estimation of their contribution. Drug Metab Dispos 40:240-248.
63. Kawakami H, Ohtsuki S, Kamiie J, Suzuki T, Abe T, and Terasaki T (2011) Simultaneous absolute quantification of 11 cytochrome P450 isoforms in human liver microsomes by liquid chromatography tandem mass spectrometry with in silico target peptide selection. J Pharm Sci 100:341-352.
64. Khojasteh SC, Prabhu S, Kenny JR, Halladay JS, and Lu AY (2011) Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur J Drug Metab Pharmacokinet 36:1-16.
65. Kilford PJ, Stringer R, Sohal B, Houston JB, and Galetin A (2009) Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDPglucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos 37:82-89.
66. Knight ZA (2010) Small molecule inhibitors of the PI3-kinase family. Curr Top Microbiol Immunol 347:263-278.
67. Knight ZA and Shokat KM (2005) Features of selective kinase inhibitors. Chem Biol 12:621-637.
68. Krishnaswamy S, Hao Q, Von Moltke LL, Greenblatt DJ, and Court MH (2004) Evaluation of 5-hydroxytryptophol and other endogenous serotonin (5-hydroxytryptamine) analogs as substrates for UDP-glucuronosyltransferase 1A6. Drug Metab Dispos 32:862-869.
69. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, and Hall SD, et al. (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383-391.
70. Kumar V, Brundage RC, Oetting WS, Leppik IE, and Tracy TS (2008) Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos 36:1242-1248.
71. Lamb DC, Waterman MR, Kelly SL, and Guengerich FP (2007) Cytochromes P450 and drug discovery. Curr Opin Biotechnol 18:504-512.
72. Leeder JS, Gaedigk R, Marcucci KA, Gaedigk A, Vyhlidal CA, Schindel BP, and Pearce RE (2005) Variability of CYP3A7 expression in human fetal liver. J Pharmacol Exp Ther 314:626-635.
73. Lépine J, Bernard O, Plante M, Têtu B, Pelletier G, Labrie F, Bélanger A, and Guillemette C (2004) Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J Clin Endocrinol Metab 89:5222-5232.
74. Li X, Song X, Kamenecka TM, and Cameron MD (2012) Discovery of a highly selective CYP3A4 inhibitor suitable for reaction phenotyping studies and differentiation of CYP3A4 and CYP3A5. Drug Metab Dispos 40:1803-1809.
75. Lin HL, Zhang H, Medower C, Hollenberg PF, and Johnson WW (2011) Inactivation of cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a thiophene-containing anticancer drug. Drug Metab Dispos 39:345-350.
76. Linder CD, Renaud NA, and Hutzler JM (2009) Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab Dispos 37:10-13.
77. Liu Y and Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358-364.
78. Liu YT, Hao HP, Liu CX, Wang GJ, and Xie HG (2007) Drugs as CYP3A probes, inducers, and inhibitors. Drug Metab Rev 39:699-721.
79. Liu Y, Ramírez J, House L, and Ratain MJ (2010) Comparison of the drug-drug interactions potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. Drug Metab Dispos 38:32-39.
80. Manevski N, Moreolo PS, Yli-Kauhaluoma J, and Finel M (2011) Bovine serum albumin decreases Km values of human UDP-glucuronosyltransferases 1A9 and 2B7 and increases Vmax values of UGT1A9. Drug Metab Dispos 39:2117-2129.
81. Manevski N, Troberg J, Svaluto-Moreolo P, Dziedzic K, Yli-Kauhaluoma J, and Finel M (2013) Albumin stimulates the activity of the human UDP-glucuronosyltransferases 1A7, 1A8, 1A10, 2A1 and 2B15, but the effects are enzyme and substrate dependent. PLoS ONE 8:e54767.
82. Manevski N, Yli-Kauhaluoma J, and Finel M (2012) 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 40:2192-2203.
83. Mano Y, Usui T, and Kamimura H (2006) In vitro inhibitory effects of non-steroidal antiinflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDPglucuronosyltransferase1A9-potent inhibition by niflumic acid. Biopharm Drug Dispos 27:1-6.
84. Marheineke K, Grünewald S, Christie W, and Reiländer H (1998) Lipid composition of Spodoptera frugiperda (Sf9) and Trichoplusia ni (Tn) insect cells used for baculovirus infection. FEBS Lett 441:49-52.
85. Milne AM, Burchell B, and Coughtrie MW (2011) A novel method for the immunoquantification of UDP-glucuronosyltransferases in human tissue. Drug Metab Dispos 39:2258-2263.
86. Miners JO, Knights KM, Houston JB, and Mackenzie PI (2006) In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Biochem Pharmacol 71:1531-1539.
87. Miners JO, Mackenzie PI, and Knights KM (2010) The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro-in vivo extrapolation of drug clearance and drugdrug interaction potential. Drug Metab Rev 42:196-208.
88. Mistry M and Houston JB (1987) Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab Dispos 15: 710-717.
89. Moriwaki Y, Yamamoto T, Takahashi S, Tsutsumi Z, and Hada T (2001) Widespread cellular distribution of aldehyde oxidase in human tissues found by immunohistochemistry staining. Histol Histopathol 16:745-753.
90. Murai T, Samata N, Iwabuchi H, and Ikeda T (2006) Human UDP-glucuronosyltransferase, UGT1A8, glucuronidates dihydrotestosterone to a monoglucuronide and further to a structurally novel diglucuronide. Drug Metab Dispos 34:1102-1108.
91. Mutlib AE, Goosen TC, Bauman JN, Williams JA, Kulkarni S, and Kostrubsky S (2006) Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chem Res Toxicol 19: 701-709.
92. Nakajima M, Tane K, Nakamura S, Shimada N, Yamazaki H, and Yokoi T (2002) Evaluation of approach to predict the contribution of multiple cytochrome P450s in drug metabolism using relative activity factor: effects of the differences in expression levels of NADPH-cytochrome P450 reductase and cytochrome b(5) in the expression system and the differences in the marker activities. J Pharm Sci 91:952-963.
93. Newton DJ, Wang RW, and Lu AY (1995) Cytochrome P450 inhibitors. Evaluation of specificities in the in vitrometabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 23:154-158.
94. Niwa T, Murayama N, and Yamazaki H (2009) Oxidation of endobiotics mediated by xenobioticmetabolizing forms of human cytochrome. Curr Drug Metab 10:700-712.
95. Obach RS (2004) Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab Dispos 32:89-97.
96. Obach RS, Huynh P, Allen MC, and Beedham C (2004) Human liver aldehyde oxidase: inhibition by 239 drugs. J Clin Pharmacol 44:7-19.
97. Oechsler S and Skopp G (2010) An in vitro approach to estimate putative inhibition of buprenorphine and norbuprenorphine glucuronidation. Int J Legal Med 124:187-194.
98. Oleson L and Court MH (2008) Effect of the beta-glucuronidase inhibitor saccharolactone on glucuronidation by human tissue microsomes and recombinant UDP-glucuronosyltransferases. J Pharm Pharmacol 60:1175-1182.
99. th International ISSX Meeting; 2013 Sept 29-Oct 3; Toronto, ON, Canada. International Society for the Study of Xenobiotics, Washington, DC.
100. Patki KC, Von Moltke LL, and Greenblatt DJ (2003) In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab Dispos 31:938-944.
101. Pearson JT, Wahlstrom JL, Dickmann LJ, Kumar S, Halpert JR, Wienkers LC, Foti RS, and Rock DA (2007) Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene: a key role for C239 in quenching reactive intermediates. Chem Res Toxicol 20:1778-1786.
102. Price RJ, Mistry H, Wield PT, Renwick AB, Beamand JA, and Lake BG (1996) Comparison of the toxicity of allyl alcohol, coumarin and menadione in precision-cut rat, guinea-pig, cynomolgus monkey and human liver slices. Arch Toxicol 71:107-111.
103. Proctor NJ, Tucker GT, and Rostami-Hodjegan A (2004) Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 34:151-178.
104. Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, and Tran TD (2010) Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J Med Chem 53:8441-8460.
105. Raccor BS and Kaspera R (2013) Extra-hepatic isozymes from the CYP1 and CYP2 families as potential chemotherapeutic targets. Curr Top Med Chem 13:1441-1453.
106. Rettie and; AE, Fisher MB (1999) Transformation enzymes: oxidative; non-P450, in Handbook of Drug Metabolism (Woolf T ed) pp 131-151, Marcel Dekker, Inc., New York.
107. Riley RJ, McGinnity DF, and Austin RP (2005) A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metab Dispos 33:1304-1311.
108. Rowland A, Elliot DJ, Knights KM, Mackenzie PI, and Miners JO (2008a) The "albumin effect" and in vitro-in vivo extrapolation: sequestration of long-chain unsaturated fatty acids enhances phenytoin hydroxylation by human liver microsomal and recombinant cytochrome P450 2C9.Drug Metab Dispos 36:870-877.
109. Rowland A, Gaganis P, Elliot DJ, Mackenzie PI, Knights KM, and Miners JO (2007) 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 321: 137-147.
110. Rowland A, Knights KM, Mackenzie PI, and Miners JO (2008b) 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 36:1056-1062.
111. Rowland A, Knights KM, Mackenzie PI, and Miners JO (2009) Characterization of the binding of drugs to human intestinal fatty acid binding protein (IFABP): potential role of IFABP as an alternative to albumin for in vitro-in vivo extrapolation of drug kinetic parameters. Drug Metab Dispos 37:1395-1403.
112. Sahi J, Khan KK, and Black CB (2008) Aldehyde oxidase activity and inhibition in hepatocytes and cytosolic fractions from mouse, rat, monkey and human. Drug Metab Lett 2:176-183.
113. Santoro AB, Struchiner CJ, Felipe CR, Tedesco-Silva H, Medina-Pestana JO, and Suarez-Kurtz G (2013) CYP3A5 genotype, but not CYP3A41b, CYP3A422, or hematocrit, predicts tacrolimus dose requirements in Brazilian renal transplant patients. Clin Pharmacol Ther 94: 201-202.
114. Sato Y, Nagata M, Kawamura A, Miyashita A, and Usui T (2012) Protein quantification of UDPglucuronosyltransferases1A1 and 2B7 in human liver microsomes by LC-MS/MS and correlation with glucuronidation activities. Xenobiotica 42:823-829.
115. Schaefer O, Ohtsuki S, Kawakami H, Inoue T, Liehner S, Saito A, Sakamoto A, Ishiguro N, Matsumaru T, and Terasaki T, et al. (2012) Absolute quantification and differential expression of drug transporters, cytochrome P450 enzymes, and UDP-glucuronosyltransferases in cultured primary human hepatocytes. Drug Metab Dispos 40:93-103.
116. Shiraga T, Yajima K, Suzuki K, Suzuki K, Hashimoto T, Iwatsubo T, Miyashita A, and Usui T (2012) Identification of UDP-glucuronosyltransferases responsible for the glucuronidation of darexaban, an oral factor Xa inhibitor, in human liver and intestine. Drug Metab Dispos 40: 276-282.
117. Soars MG, Grime K, and Riley RJ (2006) Comparative analysis of substrate and inhibitor interactions with CYP3A4 and CYP3A5. Xenobiotica 36:287-299.
118. Soars MG, Petullo DM, Eckstein JA, Kasper SC, and Wrighton SA (2004) An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes. Drug Metab Dispos 32:140-148.
119. Sridar C, Hanna I, and Hollenberg PF (2013) Quantitation of UGT1A1 in human liver microsomes using stable isotope-labelled peptides and mass spectrometry based proteomic approaches. Xenobiotica 43:336-345.
120. Sten T, Finel M, Ask B, Rane A, and Ekström L (2009) Non-steroidal anti-inflammatory drugs interact with testosterone glucuronidation. Steroids 74:971-977.
121. Stevens JC, Hines RN, Gu C, Koukouritaki SB, Manro JR, Tandler PJ, and Zaya MJ (2003) Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther 307:573-582.
122. Strassburg CP, Manns MP, and Tukey RH (1998) Expression of the UDP-glucuronosyltransferase1A locus in human colon. Identification and characterization of the novel extrahepatic UGT1A8. J Biol Chem 273:8719-8726.
123. Strelevitz TJ, Orozco CC, and Obach RS (2012) 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 40:1441-1448.
124. Stresser DM, Broudy MI, Ho T, Cargill CE, Blanchard AP, Sharma R, Dandeneau AA, Goodwin JJ, Turner SD, and Erve JC, et al. (2004) Highly selective inhibition of human CYP3Aa in vitro by azamulin and evidence that inhibition is irreversible. Drug Metab Dispos 32:105-112.
125. Stringer RA, Strain-Damerell C, Nicklin P, and Houston JB (2009) Evaluation of recombinant cytochrome P450 enzymes as an in vitro system for metabolic clearance predictions. Drug Metab Dispos 37:1025-1034.
126. Sugihara K, Kitamura S, Tatsumi K, Asahara T, and Dohi K (1997) Differences in aldehyde oxidase activity in cytosolic preparations of human and monkey liver. Biochem Mol Biol Int 41: 1153-1160.
127. Takizawa D, Hiraoka H, Goto F, Yamamoto K, and Horiuchi R (2005) Human kidneys play an important role in the elimination of propofol. Anesthesiology 102:327-330.
128. Tang W and Stearns RA (2001) Heterotropic cooperativity of cytochrome P450 3A4 and potential drug-drug interactions. Curr Drug Metab 2:185-198.
129. Tseng E, Walsky RL, Luzietti RA, Harris JJ, Kosa RE, Goosen TC, Zientek MA, and Obach RS (2014) Relative contributions of cytochrome CYP3A4 versus CYP3A5 for CYP3A-cleared drugs assessed in vitro using a CYP3A4-selective inactivator (CYP3cide). Drug Metab Dispos 42:1163-1173.
130. Uchaipichat V,Mackenzie PI, Elliot DJ, and Miners JO (2006a) Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) "probes" for human udp-glucuronosyltransferases. Drug Metab Dispos 34:449-456.
131. Uchaipichat V, Winner LK, Mackenzie PI, Elliot DJ, Williams JA, and Miners JO (2006b) Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation. Br J Clin Pharmacol 61: 427-439.
132. VandenBrink BM, Davis JA, Pearson JT, Foti RS, Wienkers LC, and Rock DA (2012) Cytochrome p450 architecture and cysteine nucleophile placement impact raloxifene-mediated mechanism-based inactivation. Mol Pharmacol 82:835-842.
133. Venkatakrishnan K and Obach RS (2005) In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metab Dispos 33:845-852.
134. Walsky RL, Bauman JN, Bourcier K, Giddens G, Lapham K, Negahban A, Ryder TF, Obach RS, Hyland R, and Goosen TC (2012a) Optimized assays for human UDP-glucuronosyltransferase (UGT) activities: altered alamethicin concentration and utility to screen for UGT inhibitors. Drug Metab Dispos 40:1051-1065.
135. Walsky RL, Obach RS, Hyland R, Kang P, Zhou S, West M, Geoghegan KF, Helal CJ, Walker GS, and Goosen TC, et al. (2012b) Selective mechanism-based inactivation of CYP3A4 by CYP3cide (PF-04981517) and its utility as an in vitro tool for delineating the relative roles of CYP3A4 versus CYP3A5 in the metabolism of drugs. Drug Metab Dispos 40 :1686-1697.
136. Wang B, Wang J, Huang SQ, Su HH, and Zhou SF (2009) Genetic polymorphism of the human cytochrome P450 2C9 gene and its clinical significance. Curr Drug Metab 10:781-834.
137. Wang JS, Wen X, Backman JT, and Neuvonen PJ (2002) Effect of albumin and cytosol on enzyme kinetics of tolbutamide hydroxylation and on inhibition of CYP2C9 by gemfibrozil in human liver microsomes. J Pharmacol Exp Ther 302:43-49.
138. Watanabe Y, Nakajima M, and Yokoi T (2002) Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab Dispos 30:1462-1469.
139. Waters NJ, Jones R, Williams G, and Sohal B (2008) Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding. J Pharm Sci 97:4586-4595.
140. Wiener D, Doerge DR, Fang JL, Upadhyaya P, and Lazarus P (2004) Characterization of N-glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human liver: importance of UDP-glucuronosyltransferase 1A4. Drug Metab Dispos 32:72-79.
141. Wienkers LC and Heath TG (2005) Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 4:825-833.
142. Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, and Ball SE (2004) Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 32:1201-1208.
143. Wright RM, Vaitaitis GM, Weigel LK, Repine TB, McManaman JL, and Repine JE (1995) Identification of the candidate ALS2 gene at chromosome 2q33 as a human aldehyde oxidase gene. Redox Rep 1:313-321.
144. Yasuhara A, Akiba-Goto M, and Aisaka K (2005) Cloning and sequencing of the aldehyde oxidase gene from Methylobacillus sp. KY4400. Biosci Biotechnol Biochem 69:2435-2438.
145. Youdim KA, Zayed A, Dickins M, Phipps A, Griffiths M, Darekar A, Hyland R, Fahmi O, Hurst S, and Plowchalk DR, et al. (2008) Application of CYP3A4 in vitro data to predict clinical drug-drug interactions; predictions of compounds as objects of interaction. Br J Clin Pharmacol 65:680-692.
146. Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, and Humphreys WG (2005) In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 33:1729-1739.
147. Zhang H, Davis CD, Sinz MW, and Rodrigues AD (2007) Cytochrome P450 reactionphenotyping: an industrial perspective. Expert Opin Drug Metab Toxicol 3:667-687.
148. Zhang X, Liu HH, Weller P, Zheng M, Tao W, Wang J, Liao G, Monshouwer M, and Peltz G (2011) In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor. Pharmacogenomics J 11:15-24.
149. Zhou Q, Matsumoto S, Ding LR, Fischer NE, and Inaba T (2004) The comparative interaction of human and bovine serum albumins with CYP2C9 in human liver microsomes. Life Sci 75: 2145-2155.
150. Zhu HJ, Yuan SH, Fang Y, Sun XZ, Kong H, and Ge WH (2011) The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis. Pharmacogenomics J 11:237-246.
151. Zientek M, Jiang Y, Youdim K, and Obach RS (2010) In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos 38: 1322-1327.
152. Zientek M, Miller H, Smith D, Dunklee MB, Heinle L, Thurston A, Lee C, Hyland R, Fahmi O, and Burdette D (2008) Development of an in vitro drug-drug interaction assay to simultaneously monitor five cytochrome P450 isoforms and performance assessment using drug library compounds. J Pharmacol Toxicol Methods 58:206-214.
153. Zucker K, Tsaroucha A, Olson L, Esquenazi V, Tzakis A, and Miller J (1999) Evidence that tacrolimus augments the bioavailability of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit 21:35-43.