Drug efficacy and safety

 

Mitochondrial drug effects

Mitochondrial defects are associated with severe pathophysiological conditions affecting a great variety of organs and tissues. By using a systems pharmacology approach that focuses on whole-animal testing, we aim to develop drugs for balanced pathway modulation, with improved efficacy and low toxicity. In vitro models with increasing complexity, including human cell lines, 3D tissue culture/organ models, are used to identify new drug targets. Promising compounds are further investigated in whole animal disease models to both explore the mechanisms of action and to identify an optimal pharmacodynamic and pharmacokinetic profile in vivo.

A second line of research is focused on adverse bioenergetic effects of drugs. Drug-induced mitochondrial dysfunction is a major contributor to adverse reactions of pharmaceuticals. Attempts to predict mitochondrial toxicity have been unsuccessful because they have focussed on single pathways rather than the mechanisms by which drugs can interfere with the coordinated regulation of cell bioenergetics. We aim to integrate in vitro and in vivo effects of drugs that lead to mitochondrial alterations into physiologically-based pharmacokinetic and -dynamic models to translate findings from animal studies to clinical implications on drug efficacy and safety.

Recent publications

  1. Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs). Schirris TJ, Ritschel T, Bilos A, Smeitink JA, Russel FG.  Mol Pharm. 2015 Oct 6. [Epub ahead of print] PubMed PMID: 26412035.

  2. Mitochondrial ADP/ATP exchange inhibition: a novel off-target mechanism underlying ibipinabant-induced myotoxicity. Schirris TJ, Ritschel T, Herma Renkema G, Willems PH, Smeitink JA, Russel FG. Sci Rep. 2015 Sep 29;5:14533

  3. Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition.Schirris TJ, Renkema GH, Ritschel T, Voermans NC, Bilos A, van Engelen BG, Brandt U, Koopman WJ, Beyrath JD, Rodenburg RJ, Willems PH, Smeitink JA, Russel FG. Cell Metab. 2015 Sep 1;22(3):399-407. doi:10.1016/j.cmet.2015.08.002. PubMed PMID: 26331605.

  4. Gait analysis in a mouse model resembling Leigh disease. Haas R, Russel FG, Smeitink JA. Behav Brain Res. 2015 Sep 9.

  5. Modeling mitochondrial dysfunctions in the brain: from mice to men. Breuer ME, Willems PH, Russel FG, Koopman WJ, Smeitink JA. J Inherit Metab Dis. 2012 Mar;35(2):193-210.