Tenofovir Disoproxil Fumarate: Toxicity, Toxicokinetics, and Toxicogenomics Analysis After 13 Weeks of Oral Administration in Mice

Abstract

Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against 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 end points. 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, after 4 and 13 weeks, cytomegaly was observed in mice treated with 1000 mg/kg of TDF, 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.

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Figure 1. Structure of tenofovir disoproxil fumarate (TDF).

Table 1. Overview of Toxicology Parameters Following TDF Administration in Mice.

Figure 2. Histopathology of (A) normal vehicle control liver and…

Table 2. Tenofovir Toxicokinetic (TK) Data Following 1 or 91 Days of Exposure.

Table 3. enomic Changes in Kidneys of Mice Treated With 1000 mg/kg of TDF for 91 Days.^a

Table 4. Genomic Changes in Liver of Mice Treated With 1000 mg/kg of TDF for 91 Days.