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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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 36:831–839
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 39:817–825
Chandok N, Watt KDS (2010) Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc 85:451–458
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 37:1339–1354
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 79:390–405
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 29:141–144
FDA (2012) Guidance for industry: drug interaction studies – study design, data analysis, implications for dosing, and labeling recommendations. Draft guidance, Rockville
Foisy MM, Yakiwchuk EM, Hughes CA (2008) Induction effects if ritonavir: implications for drug interactions. Ann Pharmacother 42:1048–1059
Fromm MF, Busse D, Kroemer HK et al (1996) Differential induction of prehepatic and hepatic metabolism of verapamil by rifampicin. Hepatology 24:796–801
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 30:1206–1213
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 168:51–65
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 39:159–234
Hewitt NJ, LeClyse EL, Fergusson SS (2007c) Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and in vitro-in vivo correlations. Xenobiotica 37:1196–1224
Honkakoski P, Negishi M (2000) Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J 347:321–337
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 25:715–721
Jones SA, Moore LB, Shenk JL et al (2000) The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol Endocrinol 14:27–39
Kaneko A, Kato M, Endo C et al (2010) Prediction of clinical CYP3A4 induction using cryopreserved human hepatocytes. Xenobiotica 40:791–799
Kewley RJ, Whitelaw ML, Chapman-Smith A (2004) The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol 36:189–204
Koose T, Bünning P (2010) Drug Disposition. Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
LeBel M, Masson E, Guilbert E et al (1998) Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone. J Clin Pharmacol 38:1042–1050
LeClyse EL (2001) Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem Biol Interact 134:283–289
LeClyse EL, Alexandre E, Hamilton GA et al (2005) Isolation and culture of primary human hepatocytes. Methods Mol Biol 290:207–229
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 36:1013–1080
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 102:1016–1023
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 48:733–742
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 134:271–281
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 31:421–431
Marker A (2007) Multiple normalisation and statistical evaluation of gene activation in complex pharmacological processes. B.A. thesis, University of Mainz, Germany
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 37:1259–1268
Raucy JL, Lasker JM (2010) Current in vitro high throughput screening approaches to assess nuclear receptor activation. Curr Drug Metab 11:806–814
Raucy JL, Lasker JM, Lieber CS et al (1989) Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch Biochem Biophys 271:270–283
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 67:427–437
Search-LC GmbH (2010) Proprietary information. Search-LC GmbH, Heidelberg, Germany
Shou M, Hayashi M, Pan Y et al (2008) Modeling, prediction, and in vitro in vivo correlation of CYP3A4 induction. Drug Metab Dispos 36:2355–2370
Sueyoshi T, Negishi M (2001) Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu Rev Pharmacol Toxicol 41:123–143
Wang B, Sanchez RI, Franklin RB et al (2004) The involvement of CYP3A4 and CYP2C9 in the metabolism of 17α-ethinylestradiol. Drug Metab Dispos 32:1209–1212
Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369:11–23
Acknowledgments
The author would like to thank Dr. Martin Burschka for critical reading of this chapter.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer-Verlag Berlin Heidelberg
About this entry
Cite this entry
Bünning, P. (2013). Drug–Drug Interaction: Enzyme Induction. In: Vogel, H.G., Maas, J., Hock, F.J., Mayer, D. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25240-2_43
Download citation
DOI: https://doi.org/10.1007/978-3-642-25240-2_43
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-25239-6
Online ISBN: 978-3-642-25240-2
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences