The renal effects of minimally nephrotoxic doses of ibandronate and zoledronate following single and intermittent intravenous administration in rats

Rapid, intravenous (i.v.) administration of high doses of bisphosphonates has been associated with acute renal toxicity. This controlled, preclinical study over 25 weeks investigated the potential for subclinical renal damage to accumulate to clinically relevant levels when minimally nephrotoxic dos...

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Bibliographic Details
Published in:Toxicology (Amsterdam) 2003-09, Vol.191 (2), p.159-167
Main Authors: Pfister, Thomas, Atzpodien, Elke, Bauss, Frieder
Format: Article
Language:English
Subjects:
Acetylglucosamine - urine
Animals
Bisphosphonates
Creatinine - blood
Creatinine - urine
Diphosphonates - administration & dosage
Diphosphonates - toxicity
Dose-Response Relationship, Drug
Female
Glutathione Transferase - urine
Ibandronate
Ibandronic Acid
Imidazoles - administration & dosage
Imidazoles - toxicity
Infusions, Intravenous
Kidney Diseases - chemically induced
Kidney Diseases - pathology
Kidney Diseases - urine
L-Lactate Dehydrogenase - urine
Nephrotoxicity
Rats
Rats, Wistar
Renal safety
Urea - blood
Urea - urine
Zoledronate
Zoledronic Acid
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Summary:Rapid, intravenous (i.v.) administration of high doses of bisphosphonates has been associated with acute renal toxicity. This controlled, preclinical study over 25 weeks investigated the potential for subclinical renal damage to accumulate to clinically relevant levels when minimally nephrotoxic doses of ibandronate (1 mg/kg) or zoledronate (1 or 3 mg/kg) were given intermittently, with a between-dose interval of 3 weeks, or as a single dose by i.v. injection. In rats, a single dose and intermittent dosing of ibandronate resulted in a similar incidence (one of six and two of six rats, respectively) and severity score (1.0 for both) of proximal tubular degeneration and single cell necrosis. No accumulation of histopathological renal damage occurred. However, intermittent dosing of zoledronate induced a higher incidence (six of six rats) and severity score (3.0) of renal damage compared with single dosing (four of six rats and 1.3, respectively). Accumulation of renal damage was also observed for a lower intermittent dose of zoledronate (1 mg/kg) that had not exhibited histopathological renal damage when given as a single 1 mg/kg dose. Biochemical parameters confirmed these histopathological findings. In summary, the results from this study indicate that administering ibandronate intermittently provides sufficient time for regeneration of potential subclinical renal damage.
ISSN:0300-483X
1879-3185
DOI:10.1016/S0300-483X(03)00257-9