ADME/Tox Cell Lines | Biowire Spring 2011



Biowire Spring 2011 — Cell Lines — Models of Disease

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ATP-binding cassette (ABC) transporters are a family of transmembrane proteins that utilize ATP hydrolysis for translocation of substrates across membranes. Importantly, ABC transporters are known to play a crucial role in the development of multidrug resistance. Evaluation of membrane transporter pharmacology in drug absorption, disposition, and drug-drug interactions (DDI) is critical to the pharmaceutical industry’s safety evaluation of new drug entities. With this goal in mind, the three ABC transporters MDR1, BCRP, and MRP2 were selected for study. Selection was based on the considerable body of evidence supporting their crucial role in the development of multidrug resistance. Each of these transporters was independently evaluated in C2BBe1 intestinal cells, a subclone of the extensively studied Caco-2 cell line. These three transporters are expressed in the luminal membrane and are ATP-dependent efflux pumps.

The objective is to generate human knockout cell lines in relevant cell types that will clearly address the contribution of membrane transporters to the efficacy and safety of potential new drug candidates. Toward this end, Sigma® Life Science is exploiting zinc finger nuclease (ZFN) technology to selectively knockout the expression of MDR1, BCRP, and MRP2 in C2BBe1 cells for the generation of ADME toxicology cell lines. These transporter knockout cell lines are clinically significant, as they will be employed to identify the specific transporter involved in the clearance or exposure of new compounds. The development of these lines will help overcome the challenges of overlapping substrate and inhibitor specificities across transporters. The cell lines will be validated in A-B/B-A drug transporter studies. An example-testing funnel using the knockout lines and parental line is shown in Figure 1.

Figure 1. Example decision tree for substrate interaction using parental and KO transporter cell lines. 

Figure 1. Example decision tree for substrate interaction using parental and KO transporter cell lines.
Adapted from Giacomini KM, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9:215–36.


Partner with Sigma Life Science

Sigma is looking for partners in the creation of novel ADME/Tox cell lines and assays.

By applying CompoZr® Zinc Finger Nuclease (ZFN) technology, our partners can develop unique screening tools tailored to their preclinical testing needs.

We are applying zinc finger nuclease technology to the areas of:

  • Drug Metabolism
  • Drug Safety
  • Genetic Toxicology
  • Developmental and Reproductive Toxicology

 

If you are interested in partnering to develop novel genetically engineered cell lines and assays, visit sigmaaldrich.com/admetox.

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