Fialuridine

Severe fialuridine-induced toxicity induded the following ... 

Several mechanisms of fialuridine-induced hepatotoxicity have been suggested fialuridine and its metabolites inhibit mitochondrial DNA replication, leading to decreased mitochondrial DNA and mitochondrial ultrastructural defects [61]. Another mechanism suggested lies in pyruvate oxidation inhibition [62]. 

The termination of fialuridine and torcetrapib can be considered as worst case scenarios in drug development. In over 50% of all cases, project termination occurs due to less spectacular reasons such as a lack of efficacy or liberation-absorption-distribution-metabolism-excretion (LADME) problems (Figure 1.4) [65]. 

Lewis, W., Levine, E.S., Griniuviene, B., Tankersley, K.O., Colacino, J.M., Sommadossi, J.P., Watanabe, K.A. and Perrino, F.W. (1996) Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts. Proceedings of the National Academy of Sciences of the United States of America, 93, 3592-3597. 

Honkoop, P., Scholte, H.R., deMan, R. A. and Schalm, S.W. (1997) Mitochondral injury. Lessons from the fialuridine trial. Drug Safety, 17,1-7. 

Park, Y, Savarese, B., Kleiner, D. et al. (1995) Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. New England Journal of Medicine, 333, 1099-1105. 

Lee, E.-W., Lai, Y, Zhang, H. and Unadkat, J.D. (2006) Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENTl) Implications for interspecies differences in mitochondrial toxicity of fialuridine. The Journal of Biologiccd Chemistry, 281 (24), 16700-16706. 

Nucleoside analogues are drugs used to treat HIV and hepatitis. One such drug fialuridine and other drugs of this type have caused severe hepatic dysfunction. This dysfunction was characterized by fatty liver and fatal liver failure. Fialuridine caused fatal damage in 5 of 12 patients in early clinical trials. Fialuridine inhibits DNA polymerases. However, there is also DNA in the mitochondria [mitochondrial DNA (mtDNA)]. 

Fialuridine causes inhibition of mtDNA replication. This inhibition and also mutations of mtDNA, which can result from treatment with the drug, lead eventually to reduced numbers of mitochondria. 

Consequently, repeated exposure to nucleoside analogues such as fialuridine leads to impaired function of the cell because of the reduced number of functioning mitochondria. 

A great deal of information about hepatotoxicity has resulted from observed effects of pharmaceuticals, a number of which have been discontinued because of their damaging effects to the liver. An example of such a hepatotoxic compound tested as a pharmaceutical is fialuridine,... 

Approximately 105 transfected embryonic stem cells are selected. Transfected embryonic stem cells are grown on layers of y-irradiated embryonic fibroblast cells. Transfected cells are plated on G-418 resistant embryonic fibroblasts feeder layers and selected in G-418 and after 36 h they are selected in Fialuridine (FIAU) or gancyclovir. 

There are abont 200 types of cells in human tissues and all their plasma membranes and the membranes of their organelles contain transporters. The drug transporters at the organelles may well become most important in the future. This was recently documented during a dramatic Phase II trial in which the nucleoside antiviral fialuridine (FIAU) caused the death of subjects as a result of severe toxicity... 

Perhaps one of the most dramatic examples of hepatic failure and lactic acidosis associated with nucleoside analogues was that which occurred during the course of early clinical trials with an investigational nucleoside analogue fialuridine for treatment of chronic hepatitis B [95]. Seven of fifteen study patients developed progressive liver failure and lactic acidosis. Five of the patients died with severe lactic acidosis two patients underwent emergency liver transplantation and survived. Severe mitochondrial toxicity was proposed as the mechanism for this injury, based in part on the similarity of this presentation to that seen in individuals with inherited disorders of mitochondrial DNA and the presence of histopathological evidence of mitochondrial injury [94, 95]. 

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