Predicting drug-drug interactions in drug discovery: Where are we now and where are we going?

Current Opinion in Drug Discovery and Development

Volumn 8, Issue 1, 2005, Pages 51-58

  Hutzler, J Matthew ^a   Messing, Dean M ^a   Wienkers, Larry C ^a  

^a PFIZER INC   (United States)

Author keywords

Allelic variants; Atypical kinetics; Cytochrome P450; Drug discovery; Drug drug interactions

Indexed keywords

BENZBROMARONE; CARBAMAZEPINE; CELECOXIB; CYTOCHROME P450; CYTOCHROME P450 2C9; CYTOCHROME P450 INHIBITOR; DAPSONE; DICLOFENAC; FELBAMATE; FLURBIPROFEN; IBUPROFEN; PHENPROCOUMON; PHENYTOIN; QUINIDINE; TOLBUTAMIDE; WARFARIN;

BLEEDING; CRYSTAL STRUCTURE; DECISION MAKING; DRUG ABSORPTION; DRUG DETERMINATION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG RESEARCH; DRUG RESPONSE; DRUG SCREENING; DRUG SENSITIVITY; ENZYME ACTIVE SITE; ENZYME BINDING; ENZYME CONFORMATION; ENZYME INHIBITION; ENZYME KINETICS; ENZYME STRUCTURE; ENZYME SUBSTRATE; GENETIC VARIABILITY; HIGH THROUGHPUT SCREENING; HUMAN; IC 50; IN VITRO STUDY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MICHAELIS CONSTANT; MODEL; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STRUCTURE ACTIVITY RELATION;

ANIMALS; DRUG DESIGN; DRUG INTERACTIONS; FORECASTING; HUMANS; KINETICS; PHARMACEUTICAL PREPARATIONS;

EID: 12244309065     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (86)

1. Edwards IR, Aronson JK: Adverse drug reactions: Definitions, diagnosis and management. Lancet (2000) 356(9237):1255-1259.
2. Belpaire FM, Bogaert MG: Cytochrome P450: Genetic polymorphism and drug interactions. Acta Clin Belg (1996) 51(4):254-260.
3. du Souich P: In human therapy, is the drug-drug interaction or the adverse drug reaction the issue? Can J Clin Pharmacol (2001) 8(3):153-161.
4. Bertz RJ, Granneman GR: Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet (1997) 32(3):210-258.
5. Wynalda MA, Wienkers LC: Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos (1997) 25(10):1211-1214.
6. Crespi CL, Miller VP, Stresser DM: Design and application of fluorometric assays for human cytochrome P450 inhibition. Methods Enzymol (2002) 357:276-284.
7. Lewis DF, Dickins M: Quantitative structure-activity relationships (QSARs) within series of inhibitors for mammalian cytochromes P450 (CYPs). J Enzyme Inhib (2001) 16(4):321-330.
8. Kunze KL, Wienkers LC, Thummel KE, Trager WF: Warfarinfluconazole. I. Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: In vitro studies. Drug Metab Dispos (1996) 24(4):414-421.
9. i determinations for CYP3A4 inhibitors.
10. Schrag ML, Wienkers LC: Covalent alteration of the CYP3A4 active site: Evidence for multiple substrate binding domains. Arch Biochem Biophys (2001) 391(1):49-55.
11. Houston JB, Kenworthy KE: In vitro-in vivo scaling of CYP kinetic data not consistent with the classical Michaelis-Menten model. Drug Metab Dispos (2000) 28(3):246-254. This paper discusses the interpretation of atypical kinetic data.
12. Idle JR, Mahgoub A, Lancaster R, Smith RL: Hypotensive response to debrisoquine and hydroxylation phenotype. Life Sci (1978) 22(11):979-983.
13. Ingelman-Sundberg M: Pharmacogenetics of cytochrome P450 and its applications in drug therapy: The past, present and future. Trends Pharmacol Sci (2004) 25(4):193-200.
14. Pirmohamed M, Park BK: Cytochrome P450 enzyme polymorphisms and adverse drug reactions. Toxicology (2003) 192(1):23-32.
15. Smith DA, van de Waterbeemd H: Pharmacokinetics and metabolism in early drug discovery. Curr Opin Chem Biol (1999) 3(4):373-378.
16. Verras A, Kuntz ID, Ortiz de Montellano PR: Computer-assisted design of selective imidazole inhibitors for cytochrome P450 enzymes. J Med Chem (2004) 47(14):3572-3579.
17. Wanchana S, Yamashita F, Hashida M: QSAR analysis of the inhibition of recombinant CYP 3A4 activity by structurally diverse compounds using a genetic algorithm-combined partial least squares method. Pharm Res (2003) 20(9):1401-1408.
18. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G 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(7):815-832. Industry committee report on the best practices for studying DDIs.
19. Moody GC, Griffen SJ, Mather AN, McGinnity DF, Riley RJ: Fully automated analysis of activities catalysed by the major human liver cytochrome P450 (CYP) enzymes: Assessment of human CYP inhibition potential. Xenobiotica (1999) 29(1):53-75.
20. Peng SX, Barbone AG Ritchie DM: High-throughput cytochrome P450 inhibition assays by ultrafast gradient liquid chromatography with tandem mass spectrometry using monolithic columns. Rapid Commun Mass Spectrom (2003) 17(6):509-518.
21. Testino SA Jr, Patonay G: High-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal (2003) 30(5):1459-1467.
22. 50. J Biomol Screen (2002) 7(4):373-382.
23. Donato MT, Jimenez N, Castell JV, Gomez-Lechon, MJ: Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes. Drug Metab Dispos (2004) 32(6):699-706.
24. Weaver R, Graham KS, Beattie IG, Riley RJ: Cytochrome P450 inhibition using recombinant proteins and mass spectrometry/multiple reaction monitoring technology in a cassette incubation. Drug Metab Dispos (2003) 31(7):955-966.
25. Cohen LH, Remley MJ, Raunig D, Vaz AD: In vitro drug interactions of cytochrome P450: An evaluation of fluorogenic to conventional substrates. Drug Metab Dispos (2003) 31(8):1005-1015.
26. Walsky RL, Obach RS: Validated assays for human cytochrome P450 activities. Drug Metab Dispos (2004) 32(6):647-660.
27. Yuan R, Madani S, Wei XX, Reynolds K, Huang S: Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab Dispos (2002) 30(9):1311-1319.
28. Atkins WM: Implications of the allosteric kinetics of cytochrome P450s. Drug Disc Today (2004) 9(11):478-484.
29. Shou M, Dai R, Cui D, Korzekwa KR, Baillie TA, Rushmore TH: A kinetic model for the metabolic interaction of two substrates at the active site of cytochrome P450 3A4. J Biol Chem (2001) 276(3):2256-2262.
30. Korzekwa KR, Krishnamachary N, Shou M, Ogai A, Parise RA, Rettie AE, Gonzalez FJ, Tracy TS: Evaluation of atypical cytochrome P450 kinetics with two-substrate models: Evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry (1998) 37(12):4137-4147. A pioneering paper discussing kinetic modeling of atypical kinetic data.
31. Galetin A, Clarke SE, Houston JB: Multisite kinetic analysis of interactions between prototypical CYP3A4 subgroup substrates: Midazolam, testosterone and nifedipine. Drug Metab Dispos (2003) 31(9):1108-1116.
32. Yano JK, Wester MR, Schoch GA, Griffin KJ, Stout CD, Johnson EF: The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05-Å resolution. J Biol Chem (2004) 279(37):38091-38094.
33. Hutzler JM, Wienkers LC, Wahlstrom JL, Carlson TJ, Tracy TS: Activation of cytochrome P450 2C9-mediated metabolism: Mechanistic evidence in support of kinetic observations. Arch Biochem Biophys (2003) 410(1):16-24. An interesting mechanistic paper in which CYP stoichiometry is shown to be a contributing factor to CYP2C9 activation.
34. Rock DA, Perkins BN, Wahlstrom J, Jones JP: A method for determining two substrates binding in the same active site of cytochrome P450BM3: An explanation of high energy Ω product formation. Arch Biochem Biophys (2003) 416(1):9-16.
35. Wester MR, Yano JK, Schoch GA, Yang C, Griffin KJ, Stout CD, Johnson EF: The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-Å resolution. J Biol Chem (2004) 279(34):35630-35637.
36. Hummel MA, Gannett PM, Aguilar JS, Tracy TS: Effector-mediated alteration of substrate orientation in cytochrome P450 2C9. Biochemistry (2004) 43(22):7207-7214. This paper includes classical NMR T1 relaxation rate data illustrating CYP2C9 active site interactions.
37. 2+. Drug Metab Dispos (2000) 28(10):1198-1201.
38. Yamaguchi Y, Khan KK, He YA, He YQ, Halpert JR: Topological changes in the CYP3A4 active site probed with phenyldiazene: Effect of interaction with NADPH-cytochrome P450 reductase and cytochrome b5 and of site-directed mutagenesis. Drug Metab Dispos (2004) 32(1):155-161.
39. Schenkman JB, Jansson I: The many roles of cytochrome b5. Pharmacol Ther(2003) 97(2):139-152.
40. Backes WL, Kelley RW: Organization of multiple cytochrome P450s with NADPH-cytochrome P450 reductase in membranes. Pharmacol Ther (2003) 98(2):221-33.
41. Locuson CW 2nd, Wahlstrom JL, Rock DA, Rock DA, Jones JP: A new class of CYP2C9 inhibitors: Probing 2C9 specificity with high-affinity benzbromarone derivatives. Drug Metab Dispos (2003) 31(7):967-971.
42. Tang W, Steams RA, Kwei GY, Iliff SA, Miller RR, Egan MA, Yu NX, Dean DC, Kumar S, Shou M, Lin JH et al: Interaction of diclofenac and quinidine in monkeys: Stimulation of diclofenac metabolism. J Pharmacol Exp Ther (1999) 291(3):1068-1074.
43. Egnell AC, Houston B, Boyer S: In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction between felbamate and carbamazepine. J Pharmacol Exp Ther (2003) 305(3):1251-1262.
44. Tracy TS: Atypical enzyme kinetics: Their effect on in vitro-in vivo pharmacokinetic predictions and drug interactions. Curr Drug Metab (2003) 4(5):341-634.
45. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W: Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. J Am Med Assoc (2001) 286(18):2270-2279.
46. Sachse C, Brockmoller J, Bauer S, Roots I: Cytochrome P450 2D6 variants in a Caucasian population: Allele frequencies and phenotypic consequences. Am J Hum Genet (1997) 60(2):284-295.
47. Furuya H, Fernandez-Salguero P, Gregory W, Taber H, Steward A, Gonzalez FJ, Idle JR: Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics (1995) 5(6):389-392.
48. 359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics (1996) 6(4):341-349.
49. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR: Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics (1994) 4(1):39-42. A pioneering paper discussing the first observation of impaired warfarin metabolism by a CYP2C9 allelic variant.
50. Yamazaki H, Inoue K, Chiba K, Ozawa N, Kawai T, Suzuki Y, Goldstein JA, Guengerich FP, Shimada T: Comparative studies on the catalytic roles of cytochrome P450 2C9 and its Cys- and Leu-variants in the oxidation of warfarin, flurbiprofen and diclofenac by human liver microsomes. Biochem Pharmacol (1998) 56(2):243-251.
51. 359 variants: Enzyme kinetics study with seven substrates. Pharmacogenetics (2000) 10(2):95-104.
52. Lee CR, Goldstein JA, Pieper JA: Cytochrome P450 2C9 polymorphisms: A comprehensive review of the in vitro and human data. Pharmacogenetics (2002) 12(3):251-263.
53. Rodrigues AD, Rushmore TH: Cytochrome P450 Pharmacogenetics in drug development: In vitro studies and clinical consequences. Curr Drug Metab (2002) 3(3):289-309.
54. Schwarz UI: Clinical relevance of genetic polymorphisms in the human CYP2C9 gene. Eur J Clin Invest (2003) 33(Suppl 2):23-30.
55. Palkimas MP Jr, Skinner HM, Gandhi PJ, Gardner AJ: Polymorphism induced sensitivity to warfarin: A review of the literature. J Thromb Thrombol (2003) 15(3)505-212.
56. Kirchheiner J, Meineke I, Steinbach N, Meisel C, Roots I, Brockmoller J: Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: No relationship to the CYP2C9 genetic polymorphism in humans. Br J Clin Pharmacol (2003) 55(1):51-61.
57. Joffe HV, Xu R, Johnson FB, Longtine J, Kucher N, Goldhaber SZ: Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost (2004) 91(6):1123-1128.
58. Peyvandi F, Spreafico M, Siboni SM, Moia M, Mannucci PM: CYP2C9 genotypes and dose requirements during the Induction phase of oral anticoagulant therapy. Clin Pharmacol Ther (2004) 75(3):198-203.
59. Siguret V, Gouin I, Golmard JL, Geoffroy S, Andreux JP, Pautas E: Cytochrome P450 2C9 polymorphisms (CYP2C9) and warfarin maintenance dose in elderly patients. Rev Med Interne (2004) 25(4):271-274.
60. Kirchheiner J. Stormer E, Meisel C, Steinbach N, Roots I, Brockmoller J: Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics (2003) 13(8):473-480.
61. Garcia-Martin E, Martinez C, Tabares B, Frias J, Agundez JA: Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther (2004) 76(2):119-127.
62. Kirchheiner J, Ufer M, Walter EC, Kammerer B, Kahlich R, Meisel C, Schwab M, Gleiter CH, Rane A, Roots I, Brockmoller J: Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics (2004) 14(1):19-26.
63. Marks BD, Thompson DV, Goossens TA, Trubetskoy OV: High-throughput screening assays for the assessment of CYP2C9*1, CYP2C9*2, and CYP2C9*3 metabolism using fluorogenic vivid substrates. J Biomol Screen (2004) 9(5):439-449. An interesting paper that may provide a basis for drug discovery efforts to screen for genetic predisposition to DDIs.
64. Verstuyft C, Morin S, Yang J, Loriot MA, Barbu V, Kerb R, Brinkmann U, Beaune P, Jaillon P, Becquemont L: A new, rapid and robust genotyping method for CYP2C9 and MDR1. Ann Biol Clin (Paris) (2003) 61(3):305-309.
65. Pickering JW, McMillin GA, Gedge F, Hill HR, Lyon E: Flow cytometric assay for genotyping cytochrome P450 2C9 and 2C19: Comparison with a microelectronic DNA array. Am J Pharmacogenomics (2004) 4(3):199-207.
66. Wen SY, Wang H, Sun OJ, Wang SQ: Rapid detection of the known SNPs of CYP2C9 using oligonucleotide microarray. World J Gastroenterol (2003) 9(6):1342-1346.
67. Gibbs MA, Hosea NA: Factors affecting the clinical development of cytochrome P450 3A substrates. Clin Pharmacokinet (2003) 42(11):969-984.
68. Hansch C, Lien EJ, Helmer F: Structure-activity correlations in the metabolism of drugs. Arch Biochem Biophys (1968) 128(2):319-330.
69. Smith DA, Jones BC: Speculations on the substrate structure-activity relationship (SSAR) of cytochrome P450 enzymes. Biochem Pharmacol (1992) 44(11):2089-2098.
70. Afzelius L, Zamora I, Masimirembwa CM, Karlen A, Andersson TB, Mecucci S, Baroni M, Cruciani G: Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors. J Med Chem (2004) 47(4):907-914.
71. Lewis DF: Quantitative structure-activity relationships (QSARs) within the cytochrome P450 system: QSARs describing substrate binding, inhibition and induction of P450s. Inflammopharmacology (2003) 11(1):43-73.
72. Williams PA, Cosme J, Vinkovic DM, Ward A, Angove HC, Day PJ, Vonrhein C, Tickle IJ, Jhoti H: Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science (2004) 305(5684):683-686.
73. Jalaie M, Arimoto R, Gifford E, Schefzick S, Waller CL: Prediction of drug-like molecular properties: Modeling cytochrome P450 interactions. Methods Mol Biol (2004) 275:449-520.
74. Lewis DF, Dickins M, Lake BG, Goldfarb PS: Investigation of enzyme selectivity in the human CYP2C subfamily: Homology modelling of CYP2C8, CYP2C9 and CYP2C19 from the CYP2C5 crystallographic template. Drug Metabol Drug Interact (2003) 19(4):257-285.
75. Scott EE, Liu H, Qun He Y, Li W, Halpert JR: Mutagenesis and molecular dynamics suggest structural and functional roles for residues in the N-terminal portion of the cytochrome P450 2B1 I helix. Arch Biochem Biophys (2004) 423(2):266-276.
76. Jones JP, He M, Trager WF, Rettie AE: Three-dimensional quantitative structure-activity relationship for inhibitors of cytochrome P4502C9. Drug Metab Dispos (1996) 24(1):1-6.
77. Rao S, Aoyama R, Schrag M, Trager WF, Rettie A, Jones JP: A refined 3-dimensional QSAR of cytochrome P450 2C9: Computational predictions of drug interactions. J Med Chem (2000) 43(15):2789-2796.
78. Haining RL, Jones JP, Henne KR, Fisher MB, Koop DR, Trager WF, Rettie AE: Enzymatic determinants of the substrate specificity of CYP2C9: Role of B'-C loop residues in providing the π-stacking anchor site for warfarin binding. Biochemistry (1999) 38(11):3285-3292.
79. de Groot MJ, Alex AA, Jones BC: Development of a combined protein and pharmacophore model for cytochrome P450 2C9. J Med Chem (2002) 45(10):1983-1993.
80. Locuson CW 2nd, Rock DA, Jones JP: Quantitative binding models for CYP2C9 based on benzbromarone analogues. Biochemistry (2004) 43(22):6948-6958.
81. Suzuki H, Kneller MB, Rock DA, Jones JP, Trager WF, Rettie AE: Active-site characteristics of CYP2C19 and CYP2C9 probed with hydantoin and barbiturate inhibitors. Arch Biochem Biophys (2004) 429(1):1-15.
82. Szklarz GD, Halpert JR: Use of homology modeling in conjunction with site-directed mutagenesis for analysis of structure-function relationships of mammalian cytochromes P450. Life Sci (1997) 61(26):2507-2520.
83. Williams PA, Cosme J, Sridhar V, Johnson EF, McRee OE: Microsomal cytochrome P450 2C5: Comparison to microbial P450s and unique features. J Inorg Biochem (2000) 81(3):183-190.
84. Afzelius L, Zamora I, Ridderstrom M, Andersson TB, Karlen A, Masimirembwa CM: Competitive CYP2C9 inhibitors: Enzyme inhibition studies, protein homology modeling and three-dimensional quantitative structure-activity relationship analysis. Mol Pharmacol (2001) 59(4):909-919.
85. Williams PA, Cosme J, Ward A, Angove HC, Matak Vinkovic D, Jhoti H: Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature (2003) 424(6947):464-468.
86. Scott EE, White MA, He YA, Johnson EF, Stout CD, Halpert JR: Structure of mammalian cytochrome P450 2B4 complexed with 4-(4-chlorophenyl)imidazole at 1.9-Å resolution: Insight into the range of P450 conformations and the coordination of redox partner binding. J Biol Chem (2004) 279(26):27294-27301.