The National Institute of General Medical Sciences of the National Institutes of Health (NIH) have awarded the grant to develop in vivo zebrafish assays for assessing drug effects on Cytochrome (CYP) P450s. CYP profiling, a critical step in drug development, is required by the Food and Drug Administration (FDA) for all new drug approvals.
“This grant, ’Zebrafish Cytochrome P450 Assays for Assessing Drug Metabolism and Drug Safety,’ will support the Phylonix research program for assessing potential drug-to-drug interactions (DDIs) during preclinical research,” commented Patricia McGrath, Phylonix President and Chief Executive Officer. “A rapid and robust whole zebrafish CYP assay, amenable to automation in multiwell plate formats, will accelerate drug metabolism and safety profiling and reduce the possibility of costly late-stage drug development failures or product market withdrawal after commercialization,” she continued.
Many clinically relevant drug-to-drug interactions (DDIs) are associated with inhibition and/or induction of a CYP enzyme, such as 3A4. Modification of CYP activities can profoundly affect therapeutic efficacy and lead to life-threatening toxicity. Examples of costly high-profile drug withdrawals due to CYP-related DDIs include the antihistamines terfenadine and astemizole, the antihypertensive mibefradil and statins such as cerivastatin. A validated, simple, cost-effective in vivo CYP assay will be useful for profiling drug metabolism prior to performing expensive mammalian testing. Because of their genetic and physiological similarity to humans, zebrafish have been shown to be an efficient, predictive animal model for assessing drug metabolism and drug safety.
Laboratory animals are critical for defining the mechanisms of drug activity and for testing therapeutic regimens; however, only a few useful models for assessing drug metabolism have been developed. Zebrafish have several important advantages for drug screening: they are small, inexpensive to maintain, and easily bred in large numbers. Zebrafish eggs are externally fertilized and each mating produces 100-200 eggs. Single zebrafish can be maintained in fluid volumes as small as 100 microliters for the first six days of development. Chemicals can then be added directly to the fish water, permeating the intact embryos. Standard microtiter plate readers can be used for quantitation, making this format particularly attractive for high-throughput drug screening.