Bioenergetic and Metabolic Profiling in Drug Discovery and Safety

Many widely-prescribed therapeutics have “off target” effects on mitochondria that undermine function via several mechanisms.  Antibiotics and antivirals can inhibit mitochondrial biogenesis by blocking mtDNA replication or translation.  More acutely, metabolic therapeutics such as thiazolidinediones and biguanides, as well as cholesterol lowering statins, variously uncouple and/or inhibit respiration.  Retrospective analysis of drugs withdrawn from the market, and those having received a Black Box Warning because of adverse events, indicates that many are mitochondrial toxicants, and that such toxicity can fully account for the clinical disposition.  Join us for this 45-minute webinar to learn why bioenergetic and mitochondrial assessments should be done early in drug development to avoid such toxicity and to learn about suitable techniques amenable to drug discovery/development arenas.

Also discussed:

• Unanticipated mitochondrial liabilities of many types of drugs
• Why this drug-induced mitochondrial toxicity was not detected pre-clinically, and recent techniques developed to assess mitochondrial function during drug development
• Development of cytoprotective compounds that preserve viability by stabilizing mitochondrial function

References and Additional Links

Dykens, J.A. 2007.  RedOx Targets: Enzyme Systems and Drug Development Strategies for Mitochondrial Dysfunction.  Comprehensive Medicinal Chemistry II. (D.J. Triggle and J.B. Taylor, eds), Elsevier, Oxford,  pp. 1053-1087

Dykens, J.A., Will, Y. 2007. Significance of Mitochondrial Assessment in Drug Development. Drug Discovery Today, 12: 777-785.

Dykens, J.A., Marroquin, L.D, Will, Y. 2007. Strategies to reduce late stage NCE attrition due to mitochondrial toxicity: Development of a high throughput respiration screen. Expert Opinion Molecular Diagnostics, 7: 161-175.

Nadanaciva, S., Dykens, J.A., Bernal, A., Capaldi, R., Will, Y. 2007. Mitochondrial Toxicity of PPAR Agonists and Statins is Exacerbated by Combined Exposure. Toxicology and Applied Pharmacology, 223: 277-287.

Marroquin, L.D., Hynes, A., Dykens, J.A., Jamieson, J.D., Will, Y. 2007. Circumventing the Crabtree Effect: Replacing Media Glucose with Galactose Increases Susceptibility of HepG2 Cells to Mitochondrial Toxins. Toxicological Sciences, 97: 539-547.

Wallace, K.B., Starkov, AA. Mitochondrial Targets of Drug Toxicity, Annual Review of Pharmacology and Toxicology, 40: 353-388, 2000.

Amacher, D.E. Drug-associated mitochondrial toxicity and its detection. Curr Med Chem. 12:1829-39, 2005.

Informational Websites:

http://www.mitochondrial.net/

http://www.mitoresearch.org/

http://www.mitophysiology.org/

Patient Advocacy Website:

http://www.umdf.org/Index.aspx

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