Drug Interaction & Combination Studies

 

HemoGenix® is a Compliant Contract Research Service Supplier through Scientist.com   

 

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 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.

 

The usual method of detecting DDI is to perform assays that will demonstrate either an induction or inhibition of CYP450 enzymes. These might include CYP1A2, 2C9, 3A4, 2C19 and 2D6 as well as other CYP450 isoforms. However, this is essentially at the sub-cellular level and provides no information regarding potential effects seen at the cellular level on specific tissues and/or cell populations.  

 

Thanks to its development of standardized and validated ATP bioluminescence in vitro toxicity assays for different cell types and tissues using robotic delivery capabilities, HemoGenix® can provide cell-based, drug-drug interaction and combination studies with the added ability to compare the response of different cells and tissues. This is usually performed by cross-titrating two or more drugs or compounds against each other.

Compared to the dose response curves for individual drugs, combining drugs at different doses can produce several different responses. These might include:

 

  1. Little, or no effect.
  2. A stimulatory or potentiation effect. 
  3. Partial inhibitory or cytotoxic effect.
  4. Potentiated cytotoxic effect.
  5. "U"-response.


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 interactions will often produce 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. 

All of the proprietary in vitro, cell-based toxicity assays described on this website can be used for drug-drug interaction and combination studies. It should be noted that although drug-drug interactions are often performed using hepatocytes, this does not mean that other cells and tissues are not affected when two or more drugs interact. The assays for which DDI studies are available, include: 

 

Using different cell types and tissues, all of the above assays have one thing in common; they all incorporate the same standardized, highly sensitive and accurate readout namely, luciferin/luciferase-based, ATP bioluminescence. This allows the results from DDI studies to be compared directly with each other in much the same manner as is used for the HemoGenix® ComparaTOX™ Platform.

 

As stated above, drug-drug interaction and combination studies are usually performed on CYP450 enzymes derived from hepatocytes. They are often provided as part of ADME/Tox screening during early drug development. These assays are provided by HemoGenix® and are described on the Mechanism of Action Page.  

 

It should be emphasized that to date, little if any correlation has been observed between CYP450 enzyme analysis and the results from in vitro, cell-based assays.