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Drug Interaction & Drug Combination

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Drug-drug interaction (DDI) studies are usually restricted to whether a drug or compound induces or inhibits one or more enzymes of the Cytochrome P450 (CYP450) system in the mitochondria of hepatocytes. The effect can be an unwanted augmentation or decrease in the dose of a drug administered to a patient, that can lead to severe side effects. However, hepatocytes are not the only cells endowed with a CYP450 system. All cells possess this system, although not all cells will possess the same CYP450 enzymes. For example, lympho-hematopoietic cells in the bone marrow are quite capable of metabolizing 5-fluorouracil in vitro to cause stem cell toxicity and a hypocellular bone marrow. If cells outside the liver can metabolize drugs and other compounds, it follows that potential drug-drug interactions can occur in other organs and tissues at the local level and could have local cellular effects.

How is Drug-Drug Interaction Detected at the Cellular Level?

The usual method of detecting DDI is to perform assays that will demonstrate either an induction or inhibition of CYP450 enzymes. At HemoGenix®, 1A2, 2C9, 3A4, 2C19 and 2D6 as well as other CYP450 isoforms are detected. However, this is essentially at the sub-cellular level and provides no information regarding potential effects seen at the cellular level on specific cell populations. HemoGenix® has developed assays specifically designed to determine whether two or more drugs cause affects at the cellular level. The assays developed for drug-drug interaction studies are usually performed on stem cell populations:

  • HALO®-384 DDI for lympho-hematopoietic stem cells.
  • MSCGlo®-384 DDI for mesenchymal stem/stromal cells.
  • STEMGlo™-DDI for other primary stem cells and stem cell lines.
  • HepatoGlo™-DDI for hepatocytes.

When evaluated individually, a drug or other compound, may demonstrate one of four primary responses:

  1. Little, or no effect.
  2. A stimulatory or potentiation effect. 
  3. Partial inhibitory or cytotoxic effect.
  4. Cytotoxic effect.

The form of the dose response curve produced will indicate the type of response. However, when two drugs or compounds are titrated against each other, the response can be quite surprising and different to that expected. Drug-drug interaction will often be indicated by a U-shaped dose response curve, indicating that at a specific dose, the effect of one drug or compound is counteracting the effect of the other. Examples for Cimetidine and Warfarin and Cyclosporine and Verapamil are provided by navigating to Products: HALO®: HALO®-384 DDI.