Drug–Drug Interactions: Designing Development Programs and Appropriate Product Labeling

  • J. Matthew Hutzler
  • Jack Cook
  • Joseph C. Fleishaker
Chapter

Abstract

Drug–drug interactions can represent a major public health issue. Drug metabolism science has evolved to the point where interactions with cytochrome P-450 isozymes can be predicted and potentially avoided or managed, but much work remains to allow accurate prediction of non-P-450 mediated interactions. Based on preclinical data, rational clinical plans can be developed to study potential drug–drug interactions in humans and develop labeling that allows optimal usage of new drugs.

Keywords

Statin Propranolol Clopidogrel Midazolam Simvastatin 

References

  1. Anglicheau D, Legendre C, Beaune P, and Thervet E. Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics 2007; 8: 835–849.PubMedGoogle Scholar
  2. Aninat C, Piton A, Glaise D, Le CT, Langouet S, Morel F, Guguen-Guillouzo C, and Guillouzo A. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 2006; 34: 75–83.PubMedGoogle Scholar
  3. Bakken GV, Rudberg I, Christensen H, Molden E, Refsum H, and Hermann M. Metabolism of quetiapine by CYP3A4 and CYP3A5 in presence or absence of cytochrome B5. Drug Metab Dispos 2009; 37: 254–258.PubMedGoogle Scholar
  4. Becker ML, Kallewaard M, Caspers PWJ, Visser LE, Leufkens HGM, and Strick BHC. Hospitalisations and emergency department visits dues to drug–drug interactions: a literature review. Pharmacoepidemiol Drug Saf 2007; 16: 641–651.PubMedGoogle Scholar
  5. Bell L, Bickford S, Nguye PH, Wang J, He T, Zhang B, Friche Y, Zimmerlin A, Urban L, and Bojanic D. Evaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery. J Biomol Screen 2008; 13: 343–353.PubMedGoogle Scholar
  6. Benet LZ and Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71: 115–121.PubMedGoogle Scholar
  7. Berry LM and Zhao Z. An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes. Drug Metab Lett 2008; 2: 51–59.PubMedGoogle Scholar
  8. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Backman M, Ohlsson R, Postlind H, Blomquist P, and Berkenstam A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 1998; 5: 12208–12213.Google Scholar
  9. Burchell B, Soars M, Monaghan G, Cassidy A, Smith D, and Ethell B. Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases. Toxicol Lett 2000; 112–113: 333–340.PubMedGoogle Scholar
  10. Cali JJ, Ma D, Sobol M, Simpson DJ, Frackman S, Good TD, Daily WJ, and Liu D. Luminogenic cytochrome P450 assays. Expert Opin Drug Metab Toxicol 2006; 2: 629–645.PubMedGoogle Scholar
  11. Cawley GF, Batie CJ, and Backes WL. Substrate-dependent competition of different P450 isozymes for limiting NADPH-cytochrome P450 reductase. Biochemistry 1995; 34: 1244–1247.PubMedGoogle Scholar
  12. Chen Q, Ngui JS, Doss GA, Wang RW, Cai X, DiNinno FP, Blizzard TA, Hammond ML, Stearns RA, Evans DC, Baillie TA, and Tang W. Cytochrome P450 3A4-mediated bioactivation of raloxifene: irreversible enzyme inhibition and thiol adduct formation. Chem Res Toxicol 2002; 15: 907–914.PubMedGoogle Scholar
  13. Cheng Y-C and Prusoff WH. Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 1973; 23: 3099–3108.Google Scholar
  14. Chu V, Einolf HJ, Evers R, Kumar G, Moore D, Ripp S, Silva J, Sinha V, Sinz M, and Skerjanec A. In vitro and in vivo induction of cytochrome p450: a survey of the current practices and recommendations: a pharmaceutical research and manufacturers of America perspective. Drug Metab Dispos 2009; 37: 1339–1354.PubMedGoogle Scholar
  15. Cohen LH, Remley MJ, Raunig D, and Vaz ADN. In vitro drug interactions of cytochrome P450: an evaluation of fluorogenic to conventional substrates. Drug Metab Dispos 2003; 31: 1005–1015.PubMedGoogle Scholar
  16. Cook JA, Feng B, Fenner KS, Kempshall S, Liu R, Rotter C, Smith DA, Troutman MD, Ullah M, and Lee CA. Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies. Mol Pharm 2010; Apr 5;7(2): 398–411.Google Scholar
  17. Crespi CL and Stresser DM. Flurometric screening for metabolism-based drug–drug interactions. J Pharmacol Toxicol Methods 2000; 44: 325–331.PubMedGoogle Scholar
  18. Cui X, Thomas A, Gerlach V, White RE, Morrison RA, and Cheng KC. Application and interpretation of hPXR screening data: validation of reporter signal requirements for prediction of clinically relevant CYP3A4 inducers. Biochem Pharmacol 2008; 76: 680–689.PubMedGoogle Scholar
  19. Dalvie D, Kang P, Zientek M, Xiang C, Zhou S, and Obach RS. Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats. Chem Res Toxicol 2008; 21: 2260–2271.PubMedGoogle Scholar
  20. Dixit V, Haraparsad N, Desai P, and Unadkat JD. In vitro LC–MS cocktail assays to simultaneously determine human cytochrome P450 activities. Biopharm Drug Dispos 2007; 28: 257–262.PubMedGoogle Scholar
  21. Duan JZ. Applications of population pharmacokinetics in current drug labelling. J Clin Pharm Ther 2007; 32: 57–79.PubMedGoogle Scholar
  22. El-Sankary W, Gibson GG, Ayrton A, and Plant N. Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers. Drug Metab Dispos 2001; 29: 1499–1504.PubMedGoogle Scholar
  23. Fahmi OA, Maurer TS, Kish M, Cardenas E, Boldt S, and Nettleton D. A combined model for predicting CYP3A4 clinical net drug–drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro. Drug Metab Dispos 2008; 36: 1698–1708.PubMedGoogle Scholar
  24. Feng B, Mills JB, Davidson RE, Mireles RJ, Janiszewski JS, Troutman MD, and de Morais SM. In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos 2008; 36: 268–275.PubMedGoogle Scholar
  25. Feng B, Xu JJ, Bi YA, Mireles R, Davidson R, Duignan DB, Campbell S, Kostrubsky VE, Dunn MC, Smith AR, and Wang HF. Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714. Toxicol Sci 2009; 108: 492–500.PubMedGoogle Scholar
  26. Fenner KS, Troutman MD, Kempshall S, Cook JA, Ware JA, Smith DA, and Lee CA. Drug–drug mediated interactions mediated through p-glycoprotein: clinical relevance and in vitro–in vivo correlation using digoxin as a probe drug. Clin Pharmacol Ther 2009; 85: 173–181.PubMedGoogle Scholar
  27. Fontana E, Dansette PM, and Poli SM. Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity. Curr Drug Metab 2005; 6: 413–454.PubMedGoogle Scholar
  28. Foti RS and Wahlstrom JL. Prediction of CYP-mediated drug interactions in vivo using in vitro data. IDrugs 2008; 11: 900–905.PubMedGoogle Scholar
  29. Fromm MF, Kim RB, Stein CM, Wilkinson GR, and Roden DM. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine [see comments]. Circulation 1999; 99: 552–557.PubMedGoogle Scholar
  30. Galetin A, Burt H, Gibbons L, and Houston JB. Prediction of time-dependent CYP3A4 drug–drug interactions: impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition. Drug Metab Dispos 2006; 34: 166–175.PubMedGoogle Scholar
  31. Galetin A, Hinton LK, Burt H, Obach RS, and Houston JB. Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug–drug interactions for CYP3A4 cleared drugs. Curr Drug Metab 2007; 8: 685–693.PubMedGoogle Scholar
  32. Galetin A, Gertz M, and Houston JB. Potential role of intestinal first-pass metabolism in the prediction of drug–drug interactions. Expert Opin Drug Metab Toxicol 2008; 4: 909–922.PubMedGoogle Scholar
  33. Gao F, Johnson DL, Ekins S, Janiszewski J, Kelly KG, Meyer RD, and West M. Optimizing higher throughput methods to assess drug–drug interactions for CYP1A2, CYP2C9, CYP2C19, CYP2D6, rCYP2D6, and CYP3A4 in vitro using a single point IC(50). J Biomol Screen 2002; 7: 373–382.PubMedGoogle Scholar
  34. Ghanbari F, Rowland-Yeo K, Bloomer JC, Clarke SE, Lennard MS, Tucker GT, and Rostami-Hodjegan A. A critical evaluation of the experimental design of studies of mechanism based enzyme inhibition, with implications for in vitro–in vivo extrapolation. Curr Drug Metab 2006; 7: 315–334.PubMedGoogle Scholar
  35. Grim KH, Bird J, Ferguson D, and Riley RJ. Mechanism-based inhibition of cytochrome P450 enzymes: an evaluation of early decision making in vitro approaches and drug–drug interaction prediction methods. Eur J Pharm Sci 2009; 36: 175–191.Google Scholar
  36. Grimm SW, Einolf HJ, Hall SD, He K, Lim HK, Ling KH, Lu C, Nomeir AA, Seibert E, Skordos KW, Tonn GR, Van HR, Wang RW, Wong YN, Yang TJ, and Obach RS. The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos 2009; 37: 1355–1370.PubMedGoogle Scholar
  37. Guengerich FP. Update information on human P550s. Drug Metab Rev 2002; 34: 7–15.PubMedGoogle Scholar
  38. Guengerich FP. Cytochrome P450 and chemical toxicity. Chem Res Toxicol 2008; 21: 70–83.PubMedGoogle Scholar
  39. Hager WD, Fenster P, Mayersohn M, Perrier D, Graves P, Marcus FI, and Goldman S. Digoxin–quinidine interaction pharmacokinetic evaluation. N Engl J Med 1979; 300(22): 1238–1241.PubMedGoogle Scholar
  40. Hamelin BA, Bouayad A, Methot J, Jobin J, Desgagnes P, Poirier P, Allaire J, Dumesnil J, and Turgeon J. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 2000; 67: 466–477.PubMedGoogle Scholar
  41. Hariparsad N, Carr BA, Evers R, and Chu X. Comparison of immortalized Fa2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. Drug Metab Dispos 2008; 36: 1046–1055.PubMedGoogle Scholar
  42. Harmsen S, Koster AS, Beijnen JH, Schellens JH, and Meijerman I. Comparison of two immortalized human cell lines to study nuclear receptor-mediated CYP3A4 induction. Drug Metab Dispos 2008; 36: 1166–1171.PubMedGoogle Scholar
  43. Hebert MF, Roberts JP, Prueksaritanont T, and Benet LZ. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52: 453–457.PubMedGoogle Scholar
  44. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, Weimar W, and van Gelder T. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003; 74: 245–254.PubMedGoogle Scholar
  45. Hesselink DA, van Schaik RHN, van Agteren M, de Fijter JW, Hartmann A, Zeier M, Budde K, Kuypers DR, Pisarski P, Meur YL, Mamelok RD, and van Gelder T. CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients. Pharmacogenet Genomics 2008; 18: 339–348.PubMedGoogle Scholar
  46. Hollenberg PF, Kent UM, and Bumpus NN. Mechanism-based inactivation of human cytochromes p450s: experimental characterization, reactive intermediates, and clinical implications. Chem Res Toxicol 2008; 21: 189–205.PubMedGoogle Scholar
  47. Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 1994; 47: 1469–1479.PubMedGoogle Scholar
  48. Huang W, Lin YS, McConn DJ, Calamia JC, Totah RA, Isoherranen N, Glodowski M, and Thummel KE. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos 2004; 32: 1434–1445.PubMedGoogle Scholar
  49. Hutzler JM, Melton RJ, Rumsey JM, Schnute ME, Locuson CW, and Wienkers LC. Inhibition of cytochrome P450 3A4 by a pyrimidineimidazole: evidence for complex heme interactions. Chem Res Toxicol 2006; 19: 1650–1659.PubMedGoogle Scholar
  50. Ismail R and Teh LK. The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients. J Clin Pharm Ther 2006; 31: 99–109.PubMedGoogle Scholar
  51. Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, and Rostami-Hodjegan A. The Simcyp® population-based ADME simulator. Expert Opin Drug Metab Toxicol 2009; 5: 211–223.PubMedGoogle Scholar
  52. Jones DR, Gorski JC, Hamman MA, Mayhew BS, Rider S, and Hall SD. Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation. J Pharmacol Exp Ther 1999; 290: 1116–1125.PubMedGoogle Scholar
  53. Jones SA, Moore LB, Wisely GB, and Kliewer SA. Use of in vitro pregnane X receptor assays to assess CYP3A4 induction potential of drug candidates. Methods Enzymol 2002; 357: 161–170.PubMedGoogle Scholar
  54. Kalgutkar AS, Obach RS, and Maurer TS. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure–activity relationships and relationship to clinical drug–drug interactions and idiosyncratic adverse drug reactions. Curr Drug Metab 2007; 8: 407–447.PubMedGoogle Scholar
  55. Kanamitsu S, Ito K, and 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: 336–343.PubMedGoogle Scholar
  56. Kanebratt KP and Andersson TB. HepaRG cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos 2008; 36: 137–145.PubMedGoogle Scholar
  57. Kawahara I, Kato Y, Suzuki H, Achira M, Ito K, Crespi CL, and Sugiyama Y. Selective inhibition of human cytochrome P450 3A4 by N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-(1, 1-dimethylethylaminocarbonyl)-4-[(furo[2, 3-b]pyridin-5-yl)methyl]piperazin-1-yl]-4(S)-hydroxy-2(R)-phenylmethy lpentanamide and P-glycoprotein by valspodar in gene transfectant systems. Drug Metab Dispos 2000; 28: 1238–1243.PubMedGoogle Scholar
  58. Kenny JR, Chen L, McGinnity DF, Grime K, Shakesheff KM, Thomson B, and Riley R. Efficient assessment of the utility of immortalized Fa2N-4 cells for cytochrome P450 (CYP) induction studies using multiplex quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and substrate cassette methodologies. Xenobiotica 2008; 38: 1500–1517.PubMedGoogle Scholar
  59. Kim M-J, Kim H, Cha I-J, Park J-S, Shon J-H, Liu K-H, and Shin J-G. 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: 2651–2658.PubMedGoogle Scholar
  60. Kindla J, Fromm MF, and Konig J. In vitro evidence for the role of OATP and OCT uptake transporters in drug–drug interactions. Expert Opin Drug Metab Toxicol 2009; 5: 489–500.PubMedGoogle Scholar
  61. Klotz T, Sachse R, Heidrich A, Jockenhovel F, Rohde G, Wensing G, Horstmann R, and Engelmann R. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol 2001; 19: 32–39.PubMedGoogle Scholar
  62. Kongkaew C, Noyce PR, and Ashcroft DM. Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies. Ann Pharmacother 2008; 42: 1017–1025.PubMedGoogle Scholar
  63. Kostrubsky SE, Strom SC, Kalgutkar AS, Kulkarni S, Atherton J, Mireles R, Feng B, Kubik R, Hanson J, Urda E, and Mutlib AE. Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol Sci 2006; 90: 451–459.PubMedGoogle Scholar
  64. Kovarik JM, Rigaudy L, Guerret M, Gerbeau C, and Rost KL. Longitudinal assessment of a P-glycoprotein-mediated drug interaction of valspodar on digoxin. Clin Pharmacol Ther 1999; 66: 391–400.PubMedGoogle Scholar
  65. Krayenbühl JC, Vozeh S, Kondo-Oestreicher M, and Dayer P. Drug–drug interactions of the new active substances: mibefradil example. Eur J Clin Pharmacol 1999; 55: 559–565.PubMedGoogle Scholar
  66. Ku HY, Ahn HJ, Seo KA, Kim H, Oh M, Bae SK, Shin JG, Shon JH, and Liu KH. The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil. Drug Metab Dispos 2008; 36: 986–990.PubMedGoogle Scholar
  67. Kumar V, Wahlstrom JL, Rock DA, Warren CJ, Gorman LA, and Tracy TS. CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab Dispos 2006; 34: 1966–1975.PubMedGoogle Scholar
  68. Kumar V, Brundage RC, Oetting WS, Leppik IE, and Tracy TS. Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos 2008; 36: 1242–1248.PubMedGoogle Scholar
  69. LeBel M, Masson E, Guilbert E, Colborn D, Paquet F, Allard S, Vallee F, and Narang PK. Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone. J Clin Pharmacol 1998; 38: 1042–1050.PubMedGoogle Scholar
  70. Lecoeur S, Bonierbale E, Challine D, Gautier JC, Valadon P, Dansette PM, Catinot R, Ballet F, Mansuy D, and Beaune PH. Specificity of in vitro covalent binding of tienilic acid metabolites to human liver microsomes in relationship to the type of hepatotoxicity: comparison with two directly hepatotoxic drugs. Chem Res Toxicol 1994; 7: 434–442.PubMedGoogle Scholar
  71. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, and Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 1998; 102: 1016–1023.PubMedGoogle Scholar
  72. Lessard E, Yessine MA, Hamelin BA, Gauvin C, Labbe L, O’Hara G, LeBlanc J, and Turgeon J. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol 2001; 21: 175–184.PubMedGoogle Scholar
  73. Lin JH. CYP induction-mediated drug interactions: in vitro assessment and clinical implications. Pharm Res 2006; 23: 1089–1116.PubMedGoogle Scholar
  74. Linder CD, Renaud NA, and Hutzler JM. Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab Dispos 2009; 37: 10–13.PubMedGoogle Scholar
  75. Lopez-Garcia MP, Dansette PM, and Mansuy D. Thiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid. Biochemistry 1994; 33: 166–175.PubMedGoogle Scholar
  76. Lu P, Schrag ML, Slaughtetr DE, Raab CE, Shou M, and Rodrigues AD. Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor. Drug Metab Dispos 2003; 31: 1352–1360.PubMedGoogle Scholar
  77. Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, Downey A, Mudra D, Graham R, Carroll K, Xie J, Madan A, Parkinson A, Christ D, Selling B, LeCluyse E, and Gan LS. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 2002; 30: 795–804.PubMedGoogle Scholar
  78. Luo G, Guenthner T, Gan LS, and Humphreys WG. CYP3A4 induction by xenobiotics: biochemistry, experimental methods and impact on drug discovery and development. Curr Drug Metab 2004; 5: 483–505.PubMedGoogle Scholar
  79. Mayhew BS, Jones DR, and 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: 1031–1037.PubMedGoogle Scholar
  80. McDonnell PJ and Jacobs MR. Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother 2002; 36: 1331–1336.PubMedGoogle Scholar
  81. McGinnity DF, Berry AJ, Kenny JR, Grime K, and Riley RJ. Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metab Dispos 2006; 34: 1291–1300.PubMedGoogle Scholar
  82. McGinnity DF, Zhang G, Kenny JR, Hamilton GA, Otmani S, Stams KR, Haney S, Brassil P, Stresser DM, and Riley RJ. Evaluation of multiple in vitro systems for assessment of CYP3A4 induction in drug discovery: human hepatocytes, pregnane X receptor reporter gene, and Fa2N-4 and HepaRG cells. Drug Metab Dispos 2009; 37: 1259–1268.PubMedGoogle Scholar
  83. Miller VP, Stresser DM, Blanchard AP, Turner S, and Crespi CL. Fluorometric high-throughput screening for inhibitors of cytochrome P450. Ann NY Acad Sci 2000; 919: 26–32.PubMedGoogle Scholar
  84. Mills JB, Rose KA, Sadagopan N, Sahi J, and de Morais SM. Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J Pharmacol Exp Ther 2004; 309: 303–309.PubMedGoogle Scholar
  85. Neuvonen PJ, Niemi M, and Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006; 80: 565–581.PubMedGoogle Scholar
  86. Obach RS. Predicting drug–drug interactions from in vitro drug metabolism data: challenges and recent advances. Curr Opin Drug Discov Devel 2009; 12: 81–89.PubMedGoogle Scholar
  87. Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, and Tremaine LM. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug–drug interactions. J Pharmacol Exp Ther 2006; 316: 336–348.PubMedGoogle Scholar
  88. Obach RS, Walsky RL, and Venkatakrishnan K. Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug–drug interactions. Drug Metab Dispos 2007; 35: 246–255.PubMedGoogle Scholar
  89. Olinga P, Elferink MG, Draaisma AL, Merema MT, Castell JV, Perez G, and Groothuis GM. Coordinated induction of drug transporters and phase I and II metabolism in human liver slices. Eur J Pharm Sci 2008; 33: 380–389.PubMedGoogle Scholar
  90. Ortiz de Montellano PR, ed. Cytochrome P450: Structure, metabolism, and biochemistry, 3rd ed. Klower Academic/Plenum Publishers, New York, 2005.Google Scholar
  91. Pearson JT, Wahlstrom JL, Dickmann LJ, Kumar S, Halpert JR, Wienkers LC, Foti RS, and Rock DA. Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene: a key role for C239 in quenching reactive intermediates. Chem Res Toxicol 2007; 20: 1778–1786.PubMedGoogle Scholar
  92. Plumb RS, Potts WB, III, Rainville PD, Alden PG, Shave DH, Baynham G, and Mazzeo JR. Addressing the analytical throughput challenges in ADME screening using rapid ultra-performance liquid chromatography/tandem mass spectrometry methodologies. Rapid Commun Mass Spectrom 2008; 22: 2139–2152.PubMedGoogle Scholar
  93. Proctor NJ, Tucker GT, and Rostami-Hodjegan A. Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 2004; 34: 151–178.PubMedGoogle Scholar
  94. Rahman A, Korzekwa KR, Grogan J, Gonzalez FJ, and Harris JW. Selective biotransformation of taxol to 6-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 1994; 54: 5543–5546.PubMedGoogle Scholar
  95. Rajagopalan P, Mazzu A, Xia C, Dawkins R, and Sundaresan P. Effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction. J Clin Pharmacol 2003; 43(3): 260–267.PubMedGoogle Scholar
  96. Ripp SL, Mills JB, Fahmi OA, Trevena KA, Liras JL, Maurer TS, and de Morais SM. Use of immortalized human hepatocytes to predict the magnitude of clinical drug–drug interactions caused by CYP3A4 induction. Drug Metab Dispos 2006; 34: 1742–1748.PubMedGoogle Scholar
  97. Rock DA, Foti RS, and Pearson JT. The combination of chemical and antibody inhibitors for superior P450 3A inhibition in reaction phenotyping studies. Drug Metab Dispos 2008; 36: 2410–2413.PubMedGoogle Scholar
  98. Rostami-Hodjegan A and Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 2007; 6: 140–148.PubMedGoogle Scholar
  99. Rowland M and Martin SB. Kinetics of drug–drug interactions. J Pharmacokinet Biopharm 1973; 1: 553–567.Google Scholar
  100. Rowland A, Gaganis P, Elliot DJ, Mackenzie PI, Knights KM, and 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: 137–147.PubMedGoogle Scholar
  101. Roymans D, Annaert P, Van HJ, Weygers A, Noukens J, Sensenhauser C, Silva J, Van LC, Hendrickx J, Mannens G, and Meuldermans W. Expression and induction potential of cytochromes P450 in human cryopreserved hepatocytes. Drug Metab Dispos 2005; 33: 1004–1016.PubMedGoogle Scholar
  102. Schoch GA, Yano JK, Wester MR, Griffin KJ, Stout CD, and Johnson EF. Structure of human microsomal cytochrome P450 2C8. J Biol Chem 2004; 279: 9497–9503.PubMedGoogle Scholar
  103. Seithel A, Eberl S, Singer K, Auge D, Heinkele G, Wolf NB, Dorje F, Fromm MF, and Konig J. The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3. Drug Metab Dispos 2007; 35: 779–786.PubMedGoogle Scholar
  104. Shen DD, Kunze KL, and Thummel KE. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev 1997; 27: 99–127.PubMedGoogle Scholar
  105. Shirasaka Y, Sakane T, and Yamashita S. Effect of P-glycoprotein expression levels on the concentration-dependent permeability of drugs to the cell membrane. J Pharm Sci 2008; 97: 553–565.PubMedGoogle Scholar
  106. Silverman RB and George C. Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (S, E)-4-amino-5-fluoropent-2-enoic acid. Biochem Biophys Res Commun 1988; 150(3): 942–946.PubMedGoogle Scholar
  107. Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CD, Windass AS, and Schneck DW. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther 2004; 76: 167–177.PubMedGoogle Scholar
  108. Sinz M, Kim S, Zhu Z, Chen T, Anthony M, Dickinson K, and Rodrigues AD. Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Curr Drug Metab 2006; 7: 375–388.PubMedGoogle Scholar
  109. Smith DA. Induction and drug development. Eur J Pharm Sci 2000; 11: 185–189.PubMedGoogle Scholar
  110. Smith DA and Schmid EF. Drug withdrawals and the lessons within. Curr Opin Drug Discov Devel 2006; 9: 38–46.PubMedGoogle Scholar
  111. Taipalensuu J, Tornblom H, Lindberg G, Einarsson C, Sjoqvist F, Melhus H, Garberg P, Sjostrom B, Lundgren B, and Artursson P. Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. J Pharmacol Exp Ther 2001; 299: 164–170.PubMedGoogle Scholar
  112. Tamai I. Intestinal and Hepatic Transport and Metabolism: Role of Transporters in Drug Absorption. Presentation at Strategies in Oral Drug Delivery 2009. Garmisch, Germany, March 8–13, 2009.Google Scholar
  113. Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, Rose MJ, Gelmann A, Greenberg HE, De Lepeleire I, Van Hecken A, De Schepper PJ, Ebel DL, Schwartz JI, and Rodrigues AD. In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 2001; 11: 223–235.PubMedGoogle Scholar
  114. Testino SA and 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: 1459–1467.PubMedGoogle Scholar
  115. Tiberghien F and Loor F. Ranking of P-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assay. Anticancer Drugs 1996; 7: 568–578.PubMedGoogle Scholar
  116. Tomalik-Scharte D, Lazar A, Fuhr U, and Kirchheiner J. The clinical role of genetic polymorphisms in drug-metabolizing enzymes. Pharmacogenomics J 2008; 8: 4–15.PubMedGoogle Scholar
  117. Treiber A, Schneiter R, Hausler S, and Stieger B. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as a common mechanism of its interactions with cyclosporin A, rifampicin and sildenafil. Drug Metab Dispos 2007; 35: 1400–1407.PubMedGoogle Scholar
  118. Uno T, Shimizu M, Yasui-Furukori N, Sugawara K, and Tateishi T. Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status. Br J Clin Pharmacol 2006; 61: 309–314.PubMedGoogle Scholar
  119. Van den Berg HW, Desai ZR, Wilson R, Kennedy G, Bridges JM, and Shanks RG. The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol 1982; 8: 215–219.PubMedGoogle Scholar
  120. Van LM, Heydari A, Yang J, Hargreaves J, Rowland-Yeo K, Lennard MS, Tucker GT, and Rostami-Hodjegan A. The impact of experimental design on assessing mechanism-based inactivation of CYP2D6 by MDMA (Ecstasy). J Psychopharmacol 2006; 20: 834–841.PubMedGoogle Scholar
  121. Venkatakrishnan K, von Moltke LL, Court MH, Harmatz JS, Crespi CL, and Greenblatt DJ. 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: 1493–1504.PubMedGoogle Scholar
  122. Walsky RL and Obach RS. Validated assays for human cytochrome P450 activities. Drug Metab Dispos 2004; 32: 647–660.PubMedGoogle Scholar
  123. Walsky RL, Gaman EA, and Obach RS. Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol 2005; 45: 68–78.PubMedGoogle Scholar
  124. Walsky RL, Astuccio AV, and Obach RS. Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol 2006; 46: 1426–1438.PubMedGoogle Scholar
  125. Wang RW, Newton DJ, Liu N, Atkins WM, and Lu AY. Human cytochrome P-450 3A4: in vitro drug–drug interaction patterns are substrate-dependent. Drug Metab Dispos 2000; 28: 360–366.PubMedGoogle Scholar
  126. Wang JH, Liu ZQ, Wang W, Chen XP, Shu Y, He N, and Zhou HH. Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther 2001; 70: 42–47.PubMedGoogle Scholar
  127. Wang YH, Jones DR, and Hall SD. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos 2004; 32: 259–266.PubMedGoogle Scholar
  128. Watanabe A, Nakamura K, Okudaira N, Okazaki O, and Sudo K. Risk assessment for drug–drug interaction caused by metabolism-based inhibition of CYP3A using automated in vitro assay systems and its application in the early drug discovery process. Drug Metab Dispos 2007; 35: 1232–1238.PubMedGoogle Scholar
  129. Wienkers LC and Heath TG. Predicting in vivo drug interactions from in vitro discovery data. Nat Rev Drug Discov 2005; 4: 825–833.PubMedGoogle Scholar
  130. Wienkers LC and Stevens JC. Cytochrome P450 reaction phenotyping. In: Drug metabolizing enzymes: Cytochrome P450 and other enzymes in drug discovery and development. Edited by Lee JA, Obach RS, and Fisher MB. CRC Press, Boca Raton, 2003, pp. 255–310.Google Scholar
  131. Williams JA, Hurst SI, Bauman J, Jones BC, Hyland R, Gibbs JP, Obach RS, and Ball SE. Reaction phenotyping in drug discovery: moving forward with confidence? Curr Drug Metab 2003; 4: 527–534.PubMedGoogle Scholar
  132. Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, and Ball SE. Drug–drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 2004; 32: 1201–1208.PubMedGoogle Scholar
  133. Wrighton SA and Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22: 1–21.PubMedGoogle Scholar
  134. Wu CY and Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res 2005; 22: 11–23.PubMedGoogle Scholar
  135. Xie HG, Wood AJ, Kim RB, Stein CM, and Wilkinson GR. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 2004; 5: 243–272.PubMedGoogle Scholar
  136. Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, and Rostami-Hodjegan A. Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr Drug Metab 2008; 9: 384–394.Google Scholar
  137. Youdim KA, Lyons R, Payne L, Jones BC, and Saunders K. An automated, high-throughput, 384 well Cytochrome P450 cocktail IC50 assay using a rapid resolution LC–MS/MS end-point. J Pharm Biomed Anal 2008; 48: 92–99.PubMedGoogle Scholar
  138. Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, and Schwab M. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 2007; 8: 743–759.PubMedGoogle Scholar
  139. Zhang H, Davis CD, Sinz MW, and Rodrigues AD. Cytochrome P450 reaction-phenotyping: an industrial perspective. Expert Opin Drug Metab Toxicol 2007; 3: 667–687.PubMedGoogle Scholar
  140. Zhang L, Zhang YD, Strong JM, Reynolds KS, and Huang SM. A regulatory viewpoint on transporter-based drug interactions. Xenobiotica 2008; 38: 709–724.PubMedGoogle Scholar
  141. Zhao P. The use of hepatocytes in evaluating time-dependent inactivation of P450 in vivo. Expert Opin Drug Metab Toxicol 2008; 4: 151–164.PubMedGoogle Scholar
  142. Zhao P, Kunze KL, and Lee CA. Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes. Drug Metab Dispos 2005; 33: 853–861.PubMedGoogle Scholar
  143. Zhou S, Chan E, Lim LY, Boelsterli UA, Li SC, Wang J, Zhang Q, Huang M, and Xu A. Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab 2004; 5: 415–442.PubMedGoogle Scholar
  144. Zientek M, Miller H, Smith D, Dunklee MB, Heinle L, Thurston A, Lee C, Hyland R, Fahmi O, and Burdette D. 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 2008; 58: 206–214.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2011

Authors and Affiliations

  • J. Matthew Hutzler
  • Jack Cook
  • Joseph C. Fleishaker
    • 1
  1. 1.Pfizer, St. Louis Laboratories, Clinical ResearchSt. LouisUSA

Personalised recommendations