Elsevier

Drug Discovery Today

Volume 12, Issues 17–18, September 2007, Pages 777-785
Drug Discovery Today

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The significance of mitochondrial toxicity testing in drug development

https://doi.org/10.1016/j.drudis.2007.07.013Get rights and content

Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities. Members of diverse drug classes undermine mitochondrial function, and among the most potent are drugs that have been withdrawn from the market, or have received Black Box warnings from the FDA. To avoid mitochondrial liabilities, routine screens need to be positioned within the drug-development process. Assays for mitochondrial function, cell models that better report mitochondrial impairment, and new animal models that more faithfully reflect clinical manifestations of mitochondrial dysfunction are discussed in the context of how such data can reduce late stage attrition of drug candidates and can yield safer drugs in the future.

Section snippets

Attrition of drugs causes humanitarian and financial losses

Of the new drugs approved by the US Food and Drug Administration (FDA) between 1994 and 2006, 38 were later withdrawn from the market because of safety concerns, the majority being hepatotoxic and cardiotoxic (Figure 1) [1]. Although this represents only 2–3% of the total, such failures to predict adverse drug reactions result in unacceptable human suffering, erode trust in the regulatory process and pharmaceutical industry, and impose immense financial losses.

A decade ago, 40% of

Function of normal mitochondria

The dominant function of mitochondria is the production of >90% of the cell's energy in form of adenosine triphosphate (ATP). This double-membraned organelle contains its own DNA (mitochondrial, or mtDNA) with a genetic code that differs from that in nuclear DNA. Mitochondria also contain the requisite mechanisms to replicate and express their genome. Mitochondria replicate independently of cell division with a typical half-life of five days to several weeks depending on the tissue. Although

Drug-induced mitochondrial toxicity

Mitochondrial replication requires the capacity to replicate and express mtDNA, and mitochondrial function depends predominantly on the impermeability of the inner membrane and the catalytic integrity of the respiratory complexes. It was not until the launch of NRTIs (nucleotide reverse transcriptase inhibitors) that mitochondrial toxicity was widely accepted as causing organ toxicities. Many NRTI's inhibit the polymerase that replicates mtDNA, thereby preventing mitochondrial replication. This

Clinical presentation of drug-induced mitochondrial toxicity

Mitochondrial impairment typically affects the most aerobically poised tissues, such as kidney and heart, or tissues exposed to higher concentrations of the drug, such as the liver, because of hepatoportal absorption of oral drugs and robust capacity for bioactivation. Similarly, bio-accumulation of statins by fast twitch skeletal muscle cells puts this fiber type at particular risk of mitochondrially induced rhabdomyolysis [38].

As mitochondrial function declines, cells respond to the loss of

Pre-clinical detection of drug-induced mitochondrial toxicity

Appreciation of the importance of drug-induced mitochondrial toxicity has recently accelerated, fostered by the development of techniques conducive to drug-development efforts. For example, the vast majority of immortalized cell lines used to evaluate drug toxicity pre-clinically are derived from cancers and are typically grown under culture conditions of supraphysiological glucose concentrations 42, 43. However, despite the presence of metabolically competent mitochondria, cells grown under

Mitochondrial testing in drug development

In order to increase drug safety and reduce attrition rates, pharmaceutical companies have started to explore and adopt newer in vivo, in vitro, and in silico tools, as well as new technologies such as the ‘omics’ platforms [72]. In addition, many limited duration teams and consortia have been formed to tackle specific issues such as hepatotoxicity, carcinogenicity, and vasculitis [http://www.fda.gov/bbs/topics/news/2006/NEW01337.html, http://rarediseasesnetwork.epi.usf.edu].

In large

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