In vitro approaches to investigate cytochrome P450 activities: Update on current status and their applicability

Expert Opinion on Drug Metabolism and Toxicology

Volumn 9, Issue 9, 2013, Pages 1097-1113

  Ong, Chin Eng ^a   Pan, Yan ^b   Mak, Joon Wah ^b   Ismail, Rusli ^c  

^a MONASH UNIVERSITY MALAYSIA   (Malaysia)

^b INTERNATIONAL MEDICAL UNIVERSITY   (Malaysia)

^c INSTITUTE FOR RESEARCH IN MOLECULAR MEDICINE INFORMM   (Malaysia)

Author keywords

Cytochromes P450; Drug metabolism; Drug drug interaction; in silico modeling; in vitro methodologies; in vitro in vivo extrapolation

Indexed keywords

CYTOCHROME P450; DICLOFENAC; DIETHYLDITHIOCARBAMIC ACID; DISULFIRAM; DRUG METABOLIZING ENZYME; EZLOPITANT; FLUCONAZOLE; FLUOXETINE; FLURBIPROFEN; FLUVOXAMINE; FURAFYLLINE; IMIPRAMINE; KETOCONAZOLE; LANSOPRAZOLE; METHOXSALEN; MIDAZOLAM; PACLITAXEL; PAROXETINE; PHENACETIN; QUERCETIN; QUINIDINE; SULFAPHENAZOLE; TESTOSTERONE; THIOTEPA; TICLOPIDINE; TOLBUTAMIDE; TRANYLCYPROMINE; TROLEANDOMYCIN; UNINDEXED DRUG; WARFARIN;

ARTICLE; DRUG CLEARANCE; DRUG METABOLISM; ENZYME ACTIVITY; ENZYME SUBSTRATE; FLUORESCENCE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; IC 50; IN VITRO STUDY; IN VIVO STUDY; LIQUID CHROMATOGRAPHY; MICROSOME MEMBRANE; NONHUMAN; PREDICTION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RADIOMETRY; TANDEM MASS SPECTROMETRY;

CHROMATOGRAPHY, LIQUID; COMPUTER SIMULATION; CYTOCHROME P-450 ENZYME SYSTEM; DRUG EVALUATION, PRECLINICAL; DRUG INTERACTIONS; HUMANS; PHARMACEUTICAL PREPARATIONS; TANDEM MASS SPECTROMETRY; XENOBIOTICS;

EID: 84882386349     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2013.800482     Document Type: Article

References (100)

1. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Tox 1992;22:1-21
2. Pelkonen O. Human CYPs: in vivo and clinical aspects. Drug Metab Rev 2002;34:37-46
3. Bjornsson TD, Callahan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 2003;31:815-32
4. Wienkers LC, Heath GH. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 2005;4:825-33
5. Zlokarnik G, Grootenhuis PDJ, Watson JB. High throughput P450 screens in early drug discovery. Drug Discov Today 2005;10:1443-50
6. Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure AUC i/AUC ratios. Drug Metab Dispos 2004;32:1201-8
7. Foti RS, Wienkers LC, Wahlstrom JL. Application of cytochrome P450 drug interaction screening in drug discovery. Comb Chem High Throughput Screen 2010;13:145-58
8. Rodrigues AD, Lin JH. Screening of drug candidates for their drug-rug interaction potential. Curr Opin Chem Biol 2001;5:396-401
9. Brodie BB, Axelrod J, Cooper JR, et al. Detoxication of drugs and other foreign compounds by liver microsomes. Science 1955;121:603-4
10. Crespi CL, Miller VP. The R144C change in the CYP2C92 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics 1997;7:203-10
11. Kumar V, Rock DA, Warren CJ, et al. Enzyme source effects on CYP2C9 kinetics and inhibition. Drug Metab Dispos 2006;34:1903-
12. McGinnity DF, Tucker J, Trigg S, et al. Prediction of CYP2C9-mediated drugdrug interactions: a comparison using data from recombinant enzymes and human hepatocytes. Drug Metab Dispos 2005;33:1700-7
13. Venkatakrishnan K, von Moltke LL, Court MH, et al. Comparison between cytochrome P450 (CYP) content and relative activity approaches to scaling from cDNA-expressed CYPs to human liver microsomes: ratios of accessory proteins as sources of discrepancies between the approaches. Drug Metab Dispos 2000;28:1493-504
14. Gomez-Lechon MJ, Donato MT, Castell JV, et al. Human hepatocytes in primary culture: the choice to investigate drug metabolism in man. Curr Drug Metab 2004;5:443-62
15. Tucker GT, Houston JB, Huang SM. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential-oward a consensus. Pharm Res 2001;18:1071-80
16. Reddy A, Heimbach T, Freiwald S, et al. Validation of a semi-automated human hepatocyte assay for the determination and prediction of intrinsic clearance in discovery. J Pharm Biomed Anal 2005;37:319-26
17. Rhodes SP, Otten JN, Hingorani GP, et al. Simultaneous assessment of cytochrome P450 activity in cultured human hepatocytes for compound-mediated induction of CYP3A4, CYP2B6, and CYP1A2. J Pharmacol Toxicol Methods 2011;63:223-6
18. Pillai VC, Strom SC, Caritis SN, et al. A sensitive and specific CYP cocktail assay for the simultaneous assessment of human cytochrome P450 activities in primary cultures of human hepatocytes using LC-MS/MS. J Pharm Biomed Anal 2013;74:126-32
19. Mortelmans K, Zeiger E. The Ames Salmonella/microsome mutagenicity assay. Mutat Res 2000;455:29-60
20. Sakura A, Suzuki S, Satoh T. Improvement of the Ames test using human liver S9 preparation. In: Yan Z, Caldwell G, editors. Optimization in drug discovery: in vitro methods. Methods Pharmacol Toxicol. Humana Press, New York; 2004. p. 325-36
21. Parkinson A. An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials. Toxicol Pathol 1996;24:48-57
22. Yao C, Levy RH. Inhibition-based metabolic drug-drug interactions: predictions from in vitro data. J Pharm Sci 2002;91:1923-35
23. Yamazaki H, Ueng YF, Shimada T, et al. Roles of divalent metal ions in oxidations catalyzed by recombinant cytochrome P450 3A4 and replacement of NADPH-cytochrome P450 reductase with other flavoproteins, ferredoxin, and oxygen surrogates. Biochemistry 1995;34:8380-9
24. Schrag ML, Wienkers LC. Topological alteration of the CYP3A4 active site by the divalent cation Mg2+. Drug Metab Dispos 2000;28:1198-201
25. Hickman D, Wang JP, Wang Y, et al. Evaluation of the selectivity of in vitro probes and suitability of organic solvents for the measurement of human cytochrome P450 monooxygenase activities. Drug Metab Dispos 1998;26:207-15
26. Vuppugalla R, Chang SY, Zhang H, et al. Effect of commonly used organic solvents on the kinetics of cytochrome P450 2B6-and 2C8-dependent activity in human liver microsomes. Drug Metab Dispos 2007;35:1990-5
27. Forrester LM, Henderson CJ, Glancey MJ, et al. Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics. Biochem J 1992;281:661-7
28. Hummel MA, Tracy TS, Hutzler JM, et al. Influence of fluorescent probe size and cytochrome b5 on drug-drug interactions in CYP2C9. J Biomol Screen 2006;11:303-9
29. Margolis JM, Obach RS. Impact of nonspecific binding to microsomes and phospholipid on the inhibition of cytochrome P4502D6: implications for relating in vitro inhibition data to in vivo drug interactions. Drug Metab Dispos 2003;31(5):606-11
30. Foti RS, Wahlstrom JL. CYP2C19 Inhibition: the impact of substrate probe selection on in vitro inhibition profiles. Drug Metab Dispos 2008;36:523-8
31. Lu AYH, Wang RW, Lin JH. Cytochrome P450 in vitro reaction phenotyping: a re-evaluation of approaches used for P450 isoform identification. Drug Metab Dispos 2003;31:345-50
32. Sai Y, Dai R Yang TJ, et al. Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica 2000;20:327-43
33. Newton DJ, Wang RW, Lu AY. Cytochrome P450 inhibitors. Evaluation of specificities in the in vitrometabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 1995;23:154-8
34. Ong CE, Coulter S, Birkett DJ, et al. The xenobiotic inhibitor profile of cytochrome P4502C8. Br J Clin Pharmacol 2000;50:573-80
35. Galetin A, Ito K, Hallifax D, et al. CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions. J Pharmacol Exp Ther 2005;314:180-90
36. Friden M, Vanaja K, Nandi VN. Drug-drug interactions of antiinfective drugs: utility of fluorescence CYP inhibition assays in drug discovery. Drug Metabol Drug Interact 2006;21:163-85
37. Trubetskoy OV, Gibson JR, Marks BD. Highly miniaturized formats for in vitro drug metabolism assays using Vivid fluorescent substrates and recombinant human cytochrome P450 enzymes. J Biomol Screen 2005;10:56-66
38. Cali JJ, Ma D, Sobol M, et al. Luminogenic cytochrome P450 assays. Expert Opin Drug Metab Toxicol 2006;2:629-45
39. Schrag ML, Wienkers LC. Covalent alteration of the CYP3A4 active site: evidence for multiple substrate binding domains. Arch Biochem Biophys 2001;391:49-55
40. Jushchyshyn MI, Hutzler JM, Schrag ML, et al. Catalytic turnover of pyrene by CYP3A4: evidence that cytochrome B5 directly induces positive cooperativity. Arch Biochem Biophys 2005;438:21-8
41. Kim MJ, Kim H, Cha IJ, et al. High-throughput screening of inhibitory potential of nine cytochrome P450 enzymes in vitro using liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2005;19:2651-8
42. He F, Bi HC, Xie ZY, et al. Rapid determination of six metabolites from multiple cytochrome P450 probe substrates in human liver microsome by liquid chromatography/mass spectrometry: application to high-throughput inhibition screening of terpenoids. Rapid Commun Mass Spectrom 2007;21:635-43
43. Hatakeyama T, Chen DL, Ismagilov RF. Microgram-scale testing of reaction conditions in solution using nanoliter plugs in microfluidics with detection by MALDI-MS. J Am Chem Soc 2006;128:2518-19
44. Fung EN, Chu I, Li C, et al. Higher-throughput screening for Caco-2 permeability utilizing a multiple sprayer liquid chromatography/tandem mass spectrometry system. Rapid Commun Mass Spectrom 2003;17:2147-52
45. Turpeinen M, Uusitalo J, Jalonen J, et al. Multiple P450 substrates in a single run: rapid and comprehensive in vitro interaction assay. Eur J Pharm Sci 2005;24:123-32
46. Tolonen A, Petsalo A, Turpeinen M, et al. In vitro interaction cocktail assay for nine major cytochrome P450 enzymes with 13 probe reactions and a single LC/MSMS run: analytical validation and testing with monoclonal anti-CYP antibodies. J Mass Spectrom 2007;42:960-6
47. Kozakai K, Yamada Y, Oshikata M, et al. Reliable high-throughput method for inhibition assay of 8 cytochrome P450 isoforms using cocktail of probe substrates and stable isotope-labeled internal standards. Drug Metab Pharmacokinet 2012;27:520-9
48. Di Marco A, Marcucci I, Verdirame M, et al. Development and validation of a high-throughput radiometric CYP3A4/5 inhibition assay using tritiated testosterone. Drug Metab Dispos 2005;33:349-58
49. Di Marco A, Cellucci A, Chaudhary A, et al. High-throughput radiometric CYP2C19 inhibition assay using tritiated (S)-mephenytoin. Drug Metab Dispos 2007;35:1737-43
50. Schoch GA, Yano JK, Wester MR, et al. Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site. J Biol Chem 2004;279:9497-503
51. Wester MR, Yano JK, Schoch GA, et al. The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution. J Biol Chem 2004;279:35630-7
52. Yano JK, Wester MR, Schoch GA, et al. The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05-A resolution. J Biol Chem 2004;279:38091-4
53. Yano JK, Hsu MH, Griffin KJ, et al. Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat Struct Mol Biol 2005;12:822-3
54. Rowland P, Blaney FE, Smyth MG, et al. Crystal structure of human cytochrome P450 2D6. J Biol Chem 2006;281:7614-22
55. Sansen S, Yano JK, Reynald RL, et al. Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2. J Biol Chem 2007;282:14348-55
56. Smith BD, Sanders JL, Porubsky PR, et al. Structure of the human lung cytochrome P450 2A13. J Biol Chem 2007;282:17306-13
57. Czodrowski P, Kriegl JM, Scheuerer S, et al. Computational approaches to predict drug metabolism. Expert Opin Drug Metab Toxicol 2009;5:15-27
58. de Groot MJ, Ekins S. Pharmacophore modeling of cytochromes P450. Adv Drug Deliv Rev 2002;54:367-83
59. Ekins S, Bravi G, Binkley S, et al. Three-and four-dimensional quantitative structure activity relationship analyses of cytochrome P-450 3A4 inhibitors. J Pharmacol Exp Ther 1999;290:429-38
60. Ekins S, Bravi G, Binkley S, et al. Three-and four-dimensional- quantitative structure activity relationship (3D/4DQSAR) analyses of CYP2C9 inhibitors. Drug Metab Dispos 2000;28:94-1002
61. Sciabola S, Morao I, de Groot MJ. Pharmacophoric fingerprint method (TOPP) for 3D-QSAR modeling: application to CYP2D6 metabolic stability. J Chem Inf Model 2007;47:76-84
62. Freitas RF, Bauab RL, Montanari CA. Novel application of 2D and 3D-similarity searches to identify substrates among cytochrome P450 2C9, 2D6, and 3A4. J Chem Inf Model 2010;50:97-109
63. De Graaf C, Pospisil P, Pos W, et al. Binding mode prediction of cytochrome p450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking. J Med Chem 2005;48:2308-18
64. De Graaf C, Oostenbrink C, Keizers PHJ, et al. Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking. J Med Chem 2006;49:2417-30
65. De Rienzo F, Fanelli F, Menziani MC, et al. Theoretical investigation of substrate specificity for cytochromes P450 IA2, P450 IID6 and P450 IIIA4. J Comput Aided Mol Des 2000;14:93-116
66. Wei DQ, Wang JF, Chen C, et al. Molecular modeling of two CYP2C19 SNPs and its implications for personalized drug design. Protein Pept Lett 2008;15:27-32
67. Yu J, Paine M.J, Marechal JD, et al. In silico prediction of drug binding to CYP2D6: identification of a new metabolite of metoclopramide. Drug Metab Dispos 2006;34:1386-92
68. Locuson CW, Gannett PM, Ayscue R, et al. Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome P450 2C9. J Med Chem 2007;50:1158-65
69. Vasanthanathan P, Taboureau O, Oostenbrink C, et al. Classification of cytochrome P450 1A2 inhibitors and noninhibitors by machine learning techniques. Drug Metab Dispos 2009;37:658-64
70. Harris DL, Park JY, Gruenke L, et al. Theoretical study of the ligand-CYP2B4 complexes: effect of structure on binding free energies and heme spin state. Proteins 2004;55:895-914
71. Wang JF, Wei DQ, Li L, et al. 3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design. Biochem Biophys Res Commun 2007;355:513-19
72. Wang JF, Zhang CC, Wei DQ. Docking and molecular dynamics studies on CYP2D6. Chin Sci Bull 2010;55:1877-80
73. Dudek AZ, Arodz T, Galvez J. Computational methods in developing quantitative structure-activity relationships (QSAR): a review. Comb Chem High Throughput Screen 2006;9:213-28
74. Livingstone DJ. The characterization of chemical structures using molecular properties. A survey. J Chem Inf Comput Sci 2000;40:195-209
75. Zheng M, Luo X, Shen Q, et al. Site of metabolism prediction for six biotransformations mediated by cytochromes P450. Bioinformatics 2009;25:1251-8
76. Ekins S, Berbaum J, Harrison RK. Generation and validation of rapid computational filters for cyp2d6 and cyp3a4. Drug Metab Dispos 2003;31:1077-80
77. Leong MK, Chen YM, Chen TH. Prediction of human cytochrome P450 2B6-substrate interactions using hierarchical support vector regression approach. J Comput Chem 2009;30:1899-909
78. Vasanthanathan P, Hritz J, Taboureau O, et al. Virtual screening and prediction of site of metabolism for cytochrome P450 1A2 ligands. J Chem Inf Model 2009;49:43-52
79. Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nature Drug Discov 2006;6:140-8
80. Venkatakrishnan K, von Moltke LL, Obach RS, et al. Drug metabolism and drug interactions: application and clinical value of in vitro models. Curr Drug Metab 2003;4:423-59
81. Obach RS. Predicting clearance in humans from in vitro data. Curr Top Med Chem 2011;11:334-9
82. Houston JB, Carlile DJ. Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metab Rev 1997;29:891-922
83. Zahlten RN, Stratman FW. The isolation of hormone-sensitive rat hepatocytes by a modified enzymatic technique. Arch Biochem Biophys 1974;163:600-8
84. Ito K, Iwatsubo T, Kanamitsu S, et al. Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver. Pharmacol Rev 1998;50:387-411
85. von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther 1996;276:370-9
86. von Moltke LL, Greenblatt DJ, Duan SX, et al. Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo. J Pharm Sci 1998;87:1184-9
87. Kanamitsu S, Ito K, Sugiyama Y. Quantitative prediction of in vivo drug-drug interactions from in vitro data based on physiological pharmacokinetics: use of maximum unbound concentration of inhibitor at the inlet to the liver. Pharm Res 2000;17:336-43
88. Ito K, Brown HS, Houston JB. Database analyses for the prediction of in vivo drug-drug interactions from in vitro data. Br J Clin Pharmacol 2004;57:473-86
89. Ito K, Hallifax D, Obach RS, et al. Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement on drug-drug interactions: CYP2D6 paradigm. Drug Metab Dispos 2005;33:837-44
90. Mayhew BS, Jones DR, Hall SD. An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. Drug Metab Dispos 2000;28:1031-7
91. Galetin A, Burt H, Gibbons L, et al. Prediction of time-dependent CYP3A4 drug-drug interactions: impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition. Drug Metab Dispos 2006;34:166-75
92. Obach RS, Walsky RL, Venkatakrishnan K. Mechanism based inactivation of human cytochrome P450 enzymes and the prediction of drug-drug interactions. Drug Metab Dispos 2007;35:246-55
93. Fahmi OA, Boldt S, Kish M, et al. Prediction of drug-drug interactions from in vitro induction data: application of the relative induction score approach using cryopreserved human hepatocytes. Drug Metab Dispos 2008;36:1971-4
94. Fahmi OA, Hurst S, Plowchalk D, et al. Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab Dispos 2009;37:1658-66
95. Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab 2008;9:310-22
96. Kosugi Y, Hirabayashi H, Igari T, et al. Evaluation of cytochrome P450-mediated drug-drug interactions based on the strategies recommended by regulatory authorities. Xenobiotica 2012;42:127-38
97. von Moltke LL, Greenblatt DJ, Duan SX, et al. In vitro prediction the terfenadine-ketoconazole pharmacokinetic interaction. J Clin Pharmacol 1994;4:1222-7
98. von Moltke LL, Greenblatt DJ, Schmider J, et al. Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine and by azole antifungal agents. J Clin Pharmacol 1996;36:783-91
99. Gibbs MA, Thummel KE, Shen DD, et al. Inhibition of cytochrome P450 3A (CYP3A) in human intestinal and liver microsomes: comparison of Ki values and impact of CYP3A5 expression. Drug Metab Dispos 1999;27:180-7
100. Houston JB, Galetin A. Progress towards prediction of human pharmacokinetic parameters from in vitro technologies. Drug Metab Rev 2003;35:393-415