title: Editor's Highlight: Comparative Renal Safety Assessment of the Hepatitis B Drugs, Adefovir, Tenofovir, Telbivudine and Entecavir in Rats.
abstract: The aim of this study was to determine the relative safety of 4 antiviral drugs (telbivudine, tenofovir, adefovir, and entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Sprague Dawley rats. The antiviral drugs were administered once daily for 4 weeks by oral gavage at ∼10 and 25-40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology, and electron microscopic examination. Administration of adefovir at 11 and 28 mg/kg for 4 weeks caused functional and morphological kidney alterations in a time- and dose-dependent manner, affecting mainly the proximal tubules and suggesting a mechanism of toxicity related to mitochondrial degeneration/depletion. Of note, the observed adefovir-induced reduction of kidney function was not detected by the standard method of glomerular filtration rate (GFR) measurements (clearance rate of the endogenous marker, creatinine), thereby emphasizing the superiority of MRI in terms of sensitive detection of GFR in rats. For the low dose of 300 mg/kg of tenofovir, minor kidney effects such as nuclear enlargement in the tubular epithelium, and hyaline droplets accumulation were detected, which was also observed for the low dose (11 mg/kg) of adefovir. No assessments could be done at the higher dose of 600/1000 mg/kg tenofovir due to gastrointestinal tract toxicity which prevented treatment of the animals for longer than 1 week. Entecavir at 1 and 3 mg/kg and telbivudine at 600 and 1600 mg/kg caused no toxicologically relevant effects on the kidney.
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland; marianne.uteng@novartis.com.
authors.forename: Marianne
authors.initials: M
authors.lastname: Uteng
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mahl
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Nicolau
authors.initials: N
authors.lastname: Beckmann
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piaia
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Ledieu
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Dubost
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tritto
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Armin
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Moulin
authors.affiliation: Novartis Institutes for BioMedical Research, East Hanover, New Jersey.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Salah-Dine
authors.initials: SD
authors.lastname: Chibout
authors.affiliation: Department of Discovery and Investigative Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Pognan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D006509:Hepatitis B / Q000188:drug therapy*; D007668:Kidney / Q000000981:diagnostic imaging / Q000187:drug effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000998:Antiviral Agents
keywords: adefovir; entecavir; hepatitis B; mitochondrial toxicity.; renal function; renal toxicity; telbivudine; tenofovir