The significance of mitochondrial toxicity testing in drug development

Fluvoxamine alters the activity of energy metabolism enzymes in the brain

“…Animals received daily administration of fluvoxamine dissolved in saline solution (10,30, and 60 mg/kg, intraperitoneal), 1 mL/kg per body weight, for 14 days (n=7). Control rats received an equivalent volume of saline, 1 mL/kg (intraperitoneal), for the same period (n=7).…”

“…9 A large number of drugs that have been withdrawn from the market or whose development was discontinued due to hepatotoxicity, nephrotoxicity, or cardiotoxicity have been reported to disturb mitochondrial functions. 10 Mitochondria are intracellular organelles which play a crucial role in adenosine triphosphate (ATP) production. 11 The Krebs cycle occurs within the mitochondrial matrix and contributes to production of large amounts of ATP via mitochondrial oxidative phosphorylation, which supplies more than 95% of the total energy requirement in the cells.…”

Mitochondria as a pharmacological target: Magnum overview

“…The proposed reasons are as follows: 1) in general, mitochondria control many of the pro-death and anti-death cell signals; 2) a number of reports describe an association between patients receiving medication and effects on mitochondrial metabolism (one famous example is the mitochondrial hepatotoxic effect of VPA, the most widely prescribed antiepileptic drug worldwide); and 3) drug safety has become a priority of many pharmaceutical companies. The last 12 years have also abounded with many reviews discussing these problems (12,(20)(21)(22).…”

“…The model of mitochondrial toxicity screening proposed by Dykens and Will includes in vitro and classic assays (respiration, OXPHOS activation, membrane potential). After series selection and lead selection of the compound using these screens, compounds should have a negative response in an animal model (21).…”

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

“…8 Upon withdrawal of mitochondrial toxicants, mitochondria can successfully regenerate over one to several weeks. 14,15 The likelihood of DILI is significantly increased in patients exhibiting polymorphisms of mitochondrial DNA polymerase gamma, 16,17 superoxide dismutase 2 (which scavenges mitochondrial superoxide), 18 or specific human leukocyte antigen (HLA) markers associated with immunoallergic injury. [19][20][21][22][23] Immunoallergic injury or hypersensitivity is associated with fever, rash, eosinophilia, and antidrug antibodies and occurs rapidly on rechallenge (sometimes within hours).…”