In Vitro Evaluation of Metabolic Drug‐Drug Interactions: A Descriptive and Critical Commentary

Albert P. Li1

1 In Vitro ADMET Laboratories, Columbia, Maryland
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 4.25
DOI:  10.1002/0471140856.tx0425s33
Online Posting Date:  August, 2007
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


Adverse drug‐drug interactions represent a major challenge for the pharmaceutical industry. Recently, in vitro approaches for the evaluation of metabolism‐related drug‐drug interactions have been developed. These in vitro approaches are found to be useful in the assessment of clinical drug‐drug interaction potential of new chemical entities and to aid the understanding of clinically significant drug‐drug interactions observed with existing drugs. The general methods for the evaluation of drug‐drug interactions using in vitro, human‐based experimental systems are described and critically reviewed. Curr. Protoc. Toxicol. 33:4.25.1‐4.25.11. © 2007 by John Wiley & Sons, Inc.

Keywords: drug‐drug interactions; regulatory testing

PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Mechanism‐Based Approach for the Evaluation of Drug‐Drug Interaction Potential
  • Data Interpretation
  • Conclusion
  • Literature Cited
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
   Backman, J.T., Kyrklund, C., Neuvonen, M., and Neuvonen, P.J. 2002. Gemfibrozil greatly increases plasma concentrations of cerivastatin. Clin. Pharmacol. Ther. 72:685‐691.
   Brown, H.S., Galetin, A., Hallifax, D., and Houston, B. 2006. Prediction of in vivo drug‐drug interactions from in vivo data: Factors affecting prototypic drug‐drug interactions involving CYP2C9, CYP2D6 and CYP3A4. Clin. Pharmacokinet. 45:1035‐1050.
   Chiba, M., Jin, L., Neway, W., Vacca, J.P., Tata, J.R., Chapman, K., and Lin, J.H. 2001. P450 interaction with HIV protease inhibitors: Relationship between metabolic stability, inhibitory potency, and P450 binding spectra. Drug Metab. Dispos. 29:1‐3.
   Crespi, C.L. 1995. Xenobiotic‐metabolizing human cells as tools for pharmacological and toxicological research. Adv. Drug Res. 26:179‐235.
   Emoto, C., Murase, S., Sawada, Y., Jones, B.C., and Iwasaki, K. 2003. In vitro inhibitory effects of 1‐aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: A comparison with SKF‐525A and ketoconazole. Drug Metab. Pharmacokinet. 18:287‐295.
   Hariparsad, N., Nallani, S., Sane, R.S., Buckley, D.J., Buckley, A.R., and Desai, P.B. 2004. Induction of CYP3A4 by efavirenz in primary human hepatocytes: Comparison with rifampin and phenobarbital. J. Clin. Pharmacol. 44:1273‐1281.
   Huang, S.M., Lesko, L.J., and Williams, R.L. 1999. Assessment of the quality and quantity of drug‐drug interaction studies in recent NDA submissions: Study design and data analysis issues. J. Clin. Pharmacol. 39:1006‐1014.
   Kato, M., Tachibana, T., Ito, K., and Sugiyama, Y. 2003. Evaluation of methods for predicting drug‐drug interactions by Monte Carlo simulation. Drug Metab. Pharmacokinet. 18:121‐127.
   Kim, J.Y., Baek, M., Lee, S., Kim, S.O., Dong, M.S., Kim, B.R., and Kim, D.H. 2001. Characterization of the selectivity and mechanism of cytochrome P450 inhibition by dimethyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylenedioxybiphenyl‐2,2′‐dicarboxylate. Drug Metab. Dispos. 29:1555‐1560.
   Li, A.P. 1997. Primary hepatocyte cultures as an in vitro experimental model for the evaluation of pharmacokinetic drug‐drug interactions. Adv. Pharmacol. 43:103‐130.
   Li, A.P. 1998. Scientific basis of drug‐drug interactions: Mechanism and preclinical evaluation. Drug Inf. J. 32:657‐664.
   Li, A.P. 2001. Screening for human ADME/Tox drug properties in drug discovery. Drug Discov. Today 6:357‐366.
   Li, A.P. 2004. In vitro approaches to evaluate ADMET drug properties. Curr. Top. Med. Chem. 4:701‐706.
   Li, A.P. 2007. Human hepatocytes: Isolation, cryopreservation and applications in drug development. Chem. Biol. Interact. 168:16‐29.
   Li, A.P., Rasmussen, A., Xu, L., and Kaminski, D.L. 1995. Rifampicin induction of lidocain metabolism in cultured human hepatocytes. J. Pharmacol. Exp. Ther. 274:673‐677.
   Li, A.P., Maurel, P., Gomez‐Lechon, M.J., Cheng, L.C., and Jurima‐Romet, M. 1997. Applications of primary human hepatocytes in the evaluation of P450 induction. Chem. Biol. Interact. 107:5‐16.
   Li, A.P., Hartman, N.R., Lu, C., Collins, J.M., and Strong, J.M. 1999a. Effects of cytochrome P450 inducers on 17 alpha‐ethinyloestradiol (EE2) conjugation by primary human hepatocytes. Br. J. Clin. Pharmacol. 48:733‐742.
   Li, A.P., Gorycki, P.D., Hengstler, J.G., Kedderis, G.L., Koebe, H.G., Rahmani, R., de Sousas, G., Silva, J.M., and Skett, P. 1999b. Present status of the application of cryopreserved hepatocytes in the evaluation of xenobiotics: Consensus of an international expert panel. Chem. Biol. Interact. 121:117‐123.
   Li, A.P., Lu, C., Brent, J.A., Pham, C., Fackett, A., Ruegg, C.E., and Silber, P.M. 1999c. Cryopreserved human hepatocytes: Characterization of drug‐metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug‐drug interaction potential. Chem. Biol. Interact. 121:17‐35.
   Lillibridge, J.H., Liang, B.H., Kerr, B.M., Webber, S., Quart, B., Shetty, B.V., and Lee, C.A. 1998. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus‐protease inhibitor nelfinavir mesylate. Drug Metab. Dispos. 26:609‐616.
   Lu, A.Y.H., Wang, R.W., and Lin, J.H. 2003. Commentary: Cytochrome P450 in vitro reaction phenotyping: A re‐evaluation of approaches for P450 isoform identification. Drug Metab. Dispos. 31:345‐350.
   Lu, C., Miwa, G.T., Prakash, S.R., Gan, L.S., and Balani, S.K. 2007. A novel model for the prediction of drug‐drug interactions in humans based on in vitro cytochrome P450 phenotypic data. Drug Metab. Dispos. 35:79‐85.
   Madeira, M., Levine, M., Chang, T.K.H., Mirfazaelian, A., and Bellward, G. 2004. The effect of cimetidine on dexromethorphan O‐demethylase activity of human liver microsomes and recombinant CYP2D6. Drug Metab. Dispos. 32:460‐467.
   McGinnity, D.F., Berry, A.J., Kenny, J.R., Grime, K., and Riley, R.J. 2006. Evaluation of time‐dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metab. Dispos. 34:1291‐1300.
   Renwick, A.B., Surry, D., Price, R.J., Lake, B.G., and Evans, D.C. 2004. Metabolism of 7‐benzyloxy‐4‐trifluoromethylcoumarin by human hepatic cytochrome P450 isoforms. Xenobiotica 30:955‐969.
   Ring, B.J., Gillespie, J.S., Eckstein, J.A., and Wrighton, S.A. 2002. Identification of human cytochromes P450 responsible for atomozetine metabolism. Drug Metab. Dispos. 30:319‐323.
   Rodriques, A.D. 1999. Integrated cytochrome P450 reaction phenotyping: Attempting to bridge the gap between cDNA‐expressed cytochromes P450 and native human liver microsomes. Biochem. Pharmacol. 57:465‐480.
   Roymans, D., Van Looveren, C., Leone, A., Parker, J.B., McMillan, M., Johnson, M.D., Koganti, A., Gilissen, R., Silber, P., Mannens, G., and Meuldermans, W. 2004. Determination of cytochrome P450 1A2 and P450 3A4 induction in cryopreserved human hepatocytes. Biochem. Pharmacol. 67:427‐437.
   Roymans, D., Annaert, P., Van Houdt, J., Weygers, A., Noukens, J., Sensenhauser, C., Silva, J., van Looveren, C., Hendrickx, J., Mannens, G., and Meuldermans, W. 2005. Expression and induction potential of cytohromes P450 in human cryopreserved hepatocytes. Drug Metab. Dispos. 33:1004‐1016.
   Uttamsingh, V., Lu, C., Miwa, G., and Gan, L.S. 2005. Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab. Dispos. 33:1723‐1728.
   Vickers, A.E., Sinclair, J.R., Zollinger, M., Heitz, F., Glanzel, U., Johanson, L., and Fischer, V. 1999. Multiple cytochrome P450s involved in the metabolism of terbinafine suggest a limited potential for drug‐drug interactions. Drug Metab. Dispos. 27:1029‐1038.
   Vtric, F., Haefeli, W.E., Drewe, J., Krahenbuhl, S., and Wenk, M. 2003. Interaction of ibuprofen and probenecid with metabolizing enzyme phenotyping procedures using caffeine as the probe drug. Brit. J. Clin. Pharmacol. 55:191‐198.
   Walsh, C.T. 1984. Suicide substrates, mechanism‐based enzyme inactivators: Recent developments. Ann. Rev. Biochem. 53:493‐535.
   Wang, R.W., Newton, D.J., Liu, N., Atkins, W.M., and Lu, A.Y.H. 2000. Human cytochrome P‐450 3A4: In vitro drug‐drug interaction patterns are substrate‐dependent. Drug Metab. Dispos. 28:360‐366.
   Wen, X., Wang, J.S., Backman, J.T., Kivisto, K.T., and Neuvonen, P.J. 2001. Gemfibrozil as an inhibitor of human cytochrome P450 2C9. Drug Metab. Dispos. 29:1359‐1361.
PDF or HTML at Wiley Online Library