A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice

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Abstract

Background: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration.We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of highdose integrase inhibitors. Methods: C57BL/6 mice were fed standard water (CTRL, n=6), raltegravir-containing water (40 mg/kg/day, n=6), or dolutegravir-containing water (2.7 mg/kg/day, n=6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. Results: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p

Original languageEnglish (US)
Pages (from-to)72-76
Number of pages5
JournalAntiviral Chemistry and Chemotherapy
Volume24
Issue number2
DOIs
StatePublished - Jan 1 2015

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Integrase Inhibitors
Creatinine
Kidney
Water
Serum
Reverse Transcriptase Inhibitors
Blood Urea Nitrogen
Inbred C57BL Mouse
Nucleosides
Cations
HIV
Urine
Gene Expression
Wounds and Injuries
Pharmaceutical Preparations
Raltegravir Potassium
dolutegravir

Keywords

  • Drug interactions
  • Highly active antiretroviral therapy
  • HIV
  • Integrase inhibitor
  • Nephrotoxicity

ASJC Scopus subject areas

  • Virology
  • Drug Discovery
  • Pharmacology

Cite this

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abstract = "Background: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration.We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of highdose integrase inhibitors. Methods: C57BL/6 mice were fed standard water (CTRL, n=6), raltegravir-containing water (40 mg/kg/day, n=6), or dolutegravir-containing water (2.7 mg/kg/day, n=6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. Results: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p",
keywords = "Drug interactions, Highly active antiretroviral therapy, HIV, Integrase inhibitor, Nephrotoxicity",
author = "Michael Eadon and Hongji Zhang and Todd Skaar and Takashi Hato and Pierre Dagher and Samir Gupta and Zeruesenay Desta",
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T1 - A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice

AU - Eadon, Michael

AU - Zhang, Hongji

AU - Skaar, Todd

AU - Hato, Takashi

AU - Dagher, Pierre

AU - Gupta, Samir

AU - Desta, Zeruesenay

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration.We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of highdose integrase inhibitors. Methods: C57BL/6 mice were fed standard water (CTRL, n=6), raltegravir-containing water (40 mg/kg/day, n=6), or dolutegravir-containing water (2.7 mg/kg/day, n=6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. Results: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p

AB - Background: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration.We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of highdose integrase inhibitors. Methods: C57BL/6 mice were fed standard water (CTRL, n=6), raltegravir-containing water (40 mg/kg/day, n=6), or dolutegravir-containing water (2.7 mg/kg/day, n=6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. Results: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p

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KW - Nephrotoxicity

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