Enzyme induction can increase the metabolic clearance of a concomitantly administered drug, resulting in reduced efficacy, which may compromise the therapeutic effectiveness of a drug. Regulatory agencies such as the FDA and others recognize enzyme induction as a potential cause of drug-drug interactions.

KaLy-Cell’s induction studies assess the potential for a drug candidate to induce (up-regulate) the expression of drug-metabolizing enzymes. Our studies can be divided into two major categories:

  • In vitro studies who evaluate the enzyme induction potential of a drug candidate in primary cultures of human hepatocytes.
  • Ex vivo studies are performed with liver microsomes from treated animals, comparing enzymatic activities against suitable positive controls.

In vitro Enzyme Induction in Human Hepatocytes

KaLy-Cell excels in in vitro regulatory enzyme induction studies in primary cultures of human hepatocytes (the FDA's "gold standard"), which are conducted in accordance with the FDA's recommendation. Induction can be evaluated based on changes in gene expression (qRT-PCR analysis of mRNA levels) and/or changes in enzyme activity determined either in the hepatocytes (in situ) or in microsomes prepared from the cultured hepatocytes.  Whatever your choice, you can be certain that our strict selection criteria for the cultures used in our induction studies ensure reliable results as we demonstrated in an article published in a prominent journal (Alexandre et al., Xenobiotica 2012). Moreover KaLy-Cell is also involved in  an interlaboratory validation of the test method for predicting human hepatic biotransformation and toxicity of chemicals by assessing their potential to induce Cytochrome P450 enzymes for which a SPSF to establish a New Test Guideline has been submitted to OCDE. (Abadie-Viollon et al., TIV 2010).

Ex-vivo and in vitro enzyme induction in Animals

Studies of in vitro and ex vivo enzyme induction in the rat, mouse, dog or monkey can provide valuable information to the investigation of a drug candidate. Not only are these types of induction studies cost-effective, they can provide the following information to your investigation (Richert et al., 2008) :

  • Which prototypical CYP inducers the drug candidate resembles

  • Epigenetic tumor formation

  • Which species most closely resembles human

  • Drug-drug interactions

  • Pharmacokinetic tolerance

  • Increased elimination (auto-induction)

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