Tenofovir Disoproxil Fumarate

Abstract

Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against human immunodeficiency virus (HIV) and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50–1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology endpoints. Plasma levels and systemic exposure of tenofovir increased less than dose-proportionally, and were similar on Days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, cytomegaly was observed in mice treated with 1000 mg/kg of TDF after 4 and 13 weeks of TDF-treatment, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on Day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression.

Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice

“…However, while didanosine did not impact nerve structure, electrophysiology or sensory function in wt mice, we found TDF produced both marked large motor fiber NCV slowing and paw thermal hyperalgesia in both gp120-tg and wt mice. The 50 mg/kg/day dose of TDF we used was selected from prior pharmacokinetic and toxicity studies in mice 16,52,53 that by allometric scaling 54,55 equates to a human dose of 0.42 mg/kg/day or 29 mg/70 kg person, well within the clinical dose of 300 mg/day. There are reports of pain and other manifestations of peripheral neuropathy in some patients treated with TDF 56–58 that have been linked to mitochondrial toxicity 20,59 .…”

Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity

“…Although TFV has favorable efficacy, safety and low resistance profiles compared with other antiretroviral drugs 4 5 6 , numerous cases have been published describing acute kidney injury, tubulopathies, nephrolithiasis, chronic kidney disease and Fanconi syndrome with long-term TFV use 7 8 9 . TFV undergoes elimination from systemic circulation via a combination of glomerular filtration and active tubular secretion 10 11 . TFV can be taken up by human organic anion transporter 1 (hOAT1) and hOAT3 and efflux by the multidrug resistance protein (MRP4), respectively 11 12 13 14 .…”

“…TFV undergoes elimination from systemic circulation via a combination of glomerular filtration and active tubular secretion 10 11 . TFV can be taken up by human organic anion transporter 1 (hOAT1) and hOAT3 and efflux by the multidrug resistance protein (MRP4), respectively 11 12 13 14 . The proximal tubule is suggested as the main site of TFV-associated toxicity however the underlying mechanisms are not well understood 15 .…”

Renal Dysfunction and Tubulopathy Induced by High-Dose Tenofovir Disoproxil Fumarate in C57BL/6 Mice

“…Based on these studies, the estimated maximum dose to be tested in our study was 800 mg/kg to account for potential drug interaction consequences of TDF. Furthermore, our maximum dose was within the TDF dose range in a previous toxicokinetic study where TDF toxicity was assessed in the dose range of 50 to 1000 mg/kg [ 29 ], showing dose-dependent toxicities in mice. Considering that the highest dose investigated in this study was higher than the maximum dose approved in humans, additional studies are necessary to increase the robustness of our study findings because the Animal-to-Human Uncertainty Factor in toxicological studies is commonly set at approximately 10.…”