title: 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.
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA hanna.ng@sri.com.
authors.forename: Hanna H
authors.initials: HH
authors.lastname: Ng
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Stock
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Rausch
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bunin
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Wang
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Brill
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gow
authors.affiliation: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D007668:Kidney / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D063065:Organophosphonates / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D000068698:Tenofovir; D059550:Toxicity Tests, Subchronic; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine
keywords: kidney; liver; tenofovir; tenofovir disoproxil fumarate; toxicity; toxicogenomics; toxicokinetics