Drug-Drug Interactions

Drug-drug interactions involves inhibition and/or induction of drug metabolizing enzymes. Inhibition of drug metabolizing enzymes is a major mechanism of drug-drug interactions. The majority of these enzymes are CYPs.

CYP Inhibition Studies

These studies are conducted with HLM or recombinant enzymes, FDA-accepted probe substrates, and control inhibitors. Both IC₅₀ and K_i values can be determined, and the pre-incubation of the test article with microsomes and NADPH are used to assess time-dependent inhibition. Alternatively, we can use recombinant CYP450 enzymes with fluorogenic probe substrates in screening assays.

UGT Inhibition Studies

Recombinant UGT enzymes are used to assess the IC₅₀ values of a test article with respect to the most common isoforms.

CYP Induction Studies

Enzyme induction following drug administration can lead to enhanced clearance of co-medications or itself, causing a drug-drug interaction, therapeutic failure, patient management, and potentially other safety issues. Cryopreserved human hepatocytes from one or more donors are used to assess the potential of a compound to induce the activity of a drug metabolizing CYP. In addition to directly studying enzyme activity, we are also able to determine CYP mRNA or protein expression induction using RT-PCR or Western Analysis, respectively (two FDA-accepted validation methods) upon request by the clients.

Price Structure for Drug-drug interaction Study:

Related References to Drug-Drug Interaction:

1. Andersson, T. B., Bredberg, E., Ericsson, H., and Sjoberg, H. An evaluation of the in vitro metabolism data for predicting the clearance and drug-drug interaction potential of CYP2C9 substrates. Drug Metab Dispos, 32: 715-721, 2004.
2. Bjornsson, T. D., Callaghan, J. T., Einolf, H. J., Fischer, V., Gan, L., Grimm, S., Kao, J., King, S. P., Miwa, G., Ni, L., Kumar, G., McLeod, J., Obach, R. S., Roberts, S., Roe, A., Shah, A., Snikeris, F., Sullivan, J. T., Tweedie, D., Vega, J. M., Walsh, J., and Wrighton, S. A. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos, 31: 815-832, 2003.
3. Bjornsson, T. D., Callaghan, J. T., Einolf, H. J., Fischer, V., Gan, L., Grimm, S., Kao, J., King, S. P., Miwa, G., Ni, L., Kumar, G., McLeod, J., Obach, S. R., Roberts, S., Roe, A., Shah, A., Snikeris, F., Sullivan, J. T., Tweedie, D., Vega, J. M., Walsh, J., and Wrighton, S. A. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol, 43: 443-469, 2003.
4. Blanchard, N., Richert, L., Coassolo, P., and Lave, T. Qualitative and quantitative assessment of drug-drug interaction potential in man, based on Ki, IC50 and inhibitor concentration. Curr Drug Metab, 5: 147-156, 2004.
5. Grime, K. H., Bird, J., Ferguson, D., and Riley, R. J. 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, 36: 175-191, 2009.
6. Krippendorff, B. F., Lienau, P., Reichel, A., and Huisinga, W. Optimizing classification of drug-drug interaction potential for CYP450 isoenzyme inhibition assays in early drug discovery. J Biomol Screen, 12: 92-99, 2007.
7. Ogasawara, A., Negishi, I., Kozakai, K., and Kume, T. In vivo evaluation of drug-drug interaction via mechanism-based inhibition by macrolide antibiotics in cynomolgus monkeys. Drug Metab Dispos, 37: 2127-2136, 2009.
8. Venkatakrishnan, K., Obach, R. S., and Rostami-Hodjegan, A. Mechanism-based inactivation of human cytochrome P450 enzymes: strategies for diagnosis and drug-drug interaction risk assessment. Xenobiotica, 37: 1225-1256, 2007.
9. 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, 35: 1232-1238, 2007.
10. Zientek, M., Miller, H., Smith, D., Dunklee, M. B., 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, 58: 206-214, 2008.