Venhoff AC, Lebrecht D, Reuss FU, Heckl-Östreicher B, Wehr R, Walker UA, Venhoff N
MtDNA depletion in rat liver induced by fosalvudine tidoxil, a novel NRTI pro-drug. [JOURNAL ARTICLE]
Antimicrob Agents Chemother 2009 May 11.
Fosalvudine tidoxil is a pro-drug derived from the nucleoside reverse transcriptase inhibitor 3-deoxy-3-fluorothymidine (FLT, alovudine). FLT effectively inhibits resistant HIV-1 but its clinical development was stopped due to bone marrow and liver toxicity. In this study we examined the long term in vivo effects of fosalvudine tidoxil on mtDNA content in rats. Sprague Dawley rats received fosalvudine tidoxil (15, 40 or 100 mg/kg/day) during a period of 8 weeks by oral gavage. Didanosine (100 mg/kg/day) was used as a positive control for mitochondrial toxicity. MtDNA levels were quantified by real-time PCR in liver, gastrocnemius muscle, sciatic nerve and inguinal fat pads. In hepatic mitochondria fosalvudine tidoxil induced a significant mtDNA depletion. At doses of 15 mg/kg, 40 mg/kg and 100 mg/kg, the mean hepatic mtDNA values were 62%, 64% and 47% of control values, respectively. Rats exposed to 100 mg/kg of fosalvudine tidoxil unlike all other groups had slightly elevated serum levels of glutamate pyruvate transaminase. Didanosine induced a similar mtDNA loss (48% of control). MtDNA levels were similar between negative control and verum groups with respect to skeletal, neural and adipose tissue. Our results suggest that fosalvudine tidoxil induces a mitochondrial hepatotoxicity and that this effects warrants scrutiny in clinical trials.
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