A New Tool for Comprehensive ADME Analysis

By: Robert Gates, Biofiles Volume 6 Article 1

IdMOC or Integrated discrete Multiple Organ Co-culture is an in vitro, cell culture based experimental model for the study of intercellular communication. In conventional in vitro systems, each cell type is studied in isolation ignoring critical interactions between organs or cell types. IdMOC technology is based on the concept that multiple organs signal or communicate via the systemic circulation (i.e., blood).

The IdMOC plate consists of multiple inner wells within a large interconnecting chamber (Figure 1). Multiple cell types are first individually seeded in the inner wells and, when required, flooded with an overlying medium to facilitate well-to-well communication. Test material can be added to the overlying medium and both media and cells can be analyzed individually. Plating of hepatocytes with other organspecific cells allows evaluation of drug metabolism and organotoxicity.

Figure 1. Schematic representation of an IdMOC assay.

IdMOC technology has been successfully used in co-culturing the following cell types and can be applied to both human and animal models.

  • Hepatocytes
  • Kidney proximal tubule epithelial cells
  • Astrocytes
  • Endothelial cells
  • Airway epithelial cells
  • Various tumor cell lines (to model tumor bearing conditions)

The IdMOC system has numerous applications in drug development, such as the evaluation of drug efficacy, ADME, and toxicity. It can simultaneously evaluate the toxic potential of a drug on cells from multiple organs, examine drug stability and metabolite (hide metabolism) formation, or estimate drug distribution. By modeling multiple-organ interactions, IdMOC can examine the pharmacological (hide pharmacology) effects of a drug and its metabolites on target and off-target organs as well as evaluate drug-drug interactions (drug interactions keyword) by measuring CYP (cytochrome P450 oxidases) induction or inhibition in hepatocytes.

IdMOC can also be used for routine and high-throughput screening (HTS) of drugs with desirable ADMET (or ADME/ Tox) properties. In vitro toxicity screening using hepatocytes in conjunction with other primary cells such as cardiomyocytes (cardiotoxicity model), kidney proximal tubule epithelial cells (nephrotoxicity model), astrocytes (neurotoxicity model), endothelial cells (vascular toxicity model), and airway epithelial cells (pulmonary toxicity model) is invaluable to the drug design and discovery (early drug discovery or rationale drug discovery) process.

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  1. Li AP, Bode C, Sakai Y. A novel in vitro system, the integrated discrete multiple organ cell culture (IdMOC) system, for the evaluation of human drug toxicity: comparative cytotoxicity of tamoxifen towards normal human cells from five major organs and MCF-7 adenocarcinoma breast cancer cells. Chem Biol Interact. 2004 Nov 1;150(1):129-36.
  2. Li, AP. In vitro evaluation of metabolic drug-drug interactions: a descriptive and critical commentary. Current Protocols in Toxicology 2007 33:4.25.1- 4.25.11.

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