Drug–Drug Interaction: Enzyme Induction

Abstract

Enzyme induction in humans may lead to drug-drug interactions. Possible pharmacokinetic consequences of enzyme induction include decreased or absent bioavailability for orally administered drugs, increased hepatic clearance, or accelerated formation of active or toxic metabolites. The “gold standard” accepted for in vitro enzyme induction assays are freshly isolated human hepatocytes. A procedure for in vitro induction studies in freshly isolated human hepatocytes is described including evaluation of CYP1A2, CYP2B6, and CYP3A4 enzyme activities and mRNA levels, and an example is given.

Keywords

Human Hepatocyte Aryl Hydrocarbon Receptor Constitutive Androstane Receptor CYP3A4 Induction HepaRG Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author would like to thank Dr. Martin Burschka for critical reading of this chapter.

References

  1. Amacher DE, Schomaker SJ, Burkhardt JE (1998) The relationship among microsomal enzyme induction, liver weight and histological change in rat toxicology studies. Food Chem Toxicol 36:831–839PubMedCrossRefGoogle Scholar
  2. Amacher DE, Schomaker SJ, Burkhardt JE (2001) The relationship among microsomal enzyme induction, liver weight and histological change in beagle dog toxicology studies. Food Chem Toxicol 39:817–825PubMedCrossRefGoogle Scholar
  3. Chandok N, Watt KDS (2010) Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc 85:451–458PubMedCrossRefGoogle Scholar
  4. Chu V, Einolf HJ, Evers R et al (2009) In vitro and in vivo induction of cytochrome P450: a survey of the current practises and recommendations: a pharmaceutical research and manufacturers of America perspective. Drug Metab Dispos 37:1339–1354PubMedCrossRefGoogle Scholar
  5. Cunha GC, van Ravenzwaay B (2005) Evaluation of mechanisms inducing thyroid toxicity and the ability of the enhanced OECD test guideline 407 to detect these changes. Arch Toxicol 79:390–405PubMedCrossRefGoogle Scholar
  6. Easterbrook J, Lu C, Sakai Y et al (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 29:141–144PubMedGoogle Scholar
  7. FDA (2012) Guidance for industry: drug interaction studies – study design, data analysis, implications for dosing, and labeling recommendations. Draft guidance, RockvilleGoogle Scholar
  8. Foisy MM, Yakiwchuk EM, Hughes CA (2008) Induction effects if ritonavir: implications for drug interactions. Ann Pharmacother 42:1048–1059PubMedCrossRefGoogle Scholar
  9. Fromm MF, Busse D, Kroemer HK et al (1996) Differential induction of prehepatic and hepatic metabolism of verapamil by rifampicin. Hepatology 24:796–801PubMedCrossRefGoogle Scholar
  10. Graham RA, Downey A, Mudra D et al (2002) In vivo and in vitro induction of cytochrome P450 enzymes in beagle dogs. Drug Metab Dispos 30:1206–1213PubMedCrossRefGoogle Scholar
  11. Hewitt NJ, de Kanter R, LeClyse E (2007a) Induction of drug metabolizing enzymes: a survey of in vitro methodologies and interpretations used in the pharmaceutical industry – do they comply with FDA recommendations? Chem Biol Interact 168:51–65PubMedCrossRefGoogle Scholar
  12. Hewitt NJ, Gomez Lechon MJ, Houstan JB et al (2007b) Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Dispos 39:159–234Google Scholar
  13. Hewitt NJ, LeClyse EL, Fergusson SS (2007c) Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and in vitro-in vivo correlations. Xenobiotica 37:1196–1224PubMedCrossRefGoogle Scholar
  14. Honkakoski P, Negishi M (2000) Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J 347:321–337PubMedCrossRefGoogle Scholar
  15. Iwase M, Kurata N, Ehana R et al (2006) Evaluation of the effects of hydrophilic organic solvents on CYP3A-mediated drug-drug interaction in vitro. Hum Exp Toxicol 25:715–721PubMedCrossRefGoogle Scholar
  16. Jones SA, Moore LB, Shenk JL et al (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14:27–39PubMedCrossRefGoogle Scholar
  17. Kaneko A, Kato M, Endo C et al (2010) Prediction of clinical CYP3A4 induction using cryopreserved human hepatocytes. Xenobiotica 40:791–799PubMedCrossRefGoogle Scholar
  18. Kewley RJ, Whitelaw ML, Chapman-Smith A (2004) The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol 36:189–204PubMedCrossRefGoogle Scholar
  19. Koose T, Bünning P (2010) Drug Disposition. Sanofi-Aventis Deutschland GmbH, Frankfurt, GermanyGoogle Scholar
  20. LeBel M, Masson E, Guilbert E et al (1998) Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone. J Clin Pharmacol 38:1042–1050PubMedCrossRefGoogle Scholar
  21. LeClyse EL (2001) Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem Biol Interact 134:283–289CrossRefGoogle Scholar
  22. LeClyse EL, Alexandre E, Hamilton GA et al (2005) Isolation and culture of primary human hepatocytes. Methods Mol Biol 290:207–229Google Scholar
  23. Lee MD, Ayanoglu E, Gong L (2006) Drug-induced changes in P450 enzyme expression at the gene expression level: a new dimension to the analysis of drug-drug interactions. Xenobiotica 36:1013–1080PubMedCrossRefGoogle Scholar
  24. Lehmann JM, McKee DD, Watson MA et al (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102:1016–1023PubMedCrossRefGoogle Scholar
  25. Li AP, Hartman NR, Lu C et al (1999) Effects of cytochrome P450 inducers on 17α-ethinylestradiol (EE2) conjugation by primary human hepatocytes. Br J Clin Pharmacol 48:733–742PubMedCrossRefGoogle Scholar
  26. Lu C, Li AP (2001) Species comparison in P450 induction: effects of dexamethasone, omeprazole and rifampin on P450 isoforms 1A and 3A in primary hepatocytes from man, Sprague–Dawley rat, minipig and beagle dog. Chem Biol Interact 134:271–281PubMedCrossRefGoogle Scholar
  27. Madan A, Graham RA, Carroll KM et al (2003) Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultures human hepatocytes. Drug Metab Dispos 31:421–431PubMedCrossRefGoogle Scholar
  28. Marker A (2007) Multiple normalisation and statistical evaluation of gene activation in complex pharmacological processes. B.A. thesis, University of Mainz, GermanyGoogle Scholar
  29. McGinnity DF, Zhang G, Kenny JR et al (2009) 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 37:1259–1268PubMedCrossRefGoogle Scholar
  30. Raucy JL, Lasker JM (2010) Current in vitro high throughput screening approaches to assess nuclear receptor activation. Curr Drug Metab 11:806–814PubMedCrossRefGoogle Scholar
  31. Raucy JL, Lasker JM, Lieber CS et al (1989) Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch Biochem Biophys 271:270–283PubMedCrossRefGoogle Scholar
  32. Roymans D, Van Looveren C, Leone A et al (2005) Determination of cytochrome P450 1A2 and cytochrome P450 3A4 induction in cryopreserved human hepatocytes. Biochem Pharmacol 67:427–437CrossRefGoogle Scholar
  33. Search-LC GmbH (2010) Proprietary information. Search-LC GmbH, Heidelberg, GermanyGoogle Scholar
  34. Shou M, Hayashi M, Pan Y et al (2008) Modeling, prediction, and in vitro in vivo correlation of CYP3A4 induction. Drug Metab Dispos 36:2355–2370PubMedCrossRefGoogle Scholar
  35. Sueyoshi T, Negishi M (2001) Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu Rev Pharmacol Toxicol 41:123–143PubMedCrossRefGoogle Scholar
  36. Wang B, Sanchez RI, Franklin RB et al (2004) The involvement of CYP3A4 and CYP2C9 in the metabolism of 17α-ethinylestradiol. Drug Metab Dispos 32:1209–1212PubMedCrossRefGoogle Scholar
  37. Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369:11–23PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Sanofi Deutschland GmbHFrankfurt am MainGermany

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