Disposition and nephrotoxicity of 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD), in rats and mice

Cal, J. C.; Daley‐Yates, Peter T.

doi:10.1016/0300-483x(90)90088-x

Cited by 41 publications

(8 citation statements)

References 24 publications

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“…Similarly, a previous study with a single dose of intravenous ibandronate and zoledronate (1 mg/kg, and 1 or 3 mg/kg, respectively) in 34-week old rats showed that 4 days after dosing there was no significant change in the majority of biochemical parameters and urinary enzymes compared with controls (Pfister et al 2003). Conversely, immediate changes in renal function have been reported for pamidronate and zoledronate in an acute renal tolerability model in the rat (Cal & Daley-Yates 1990;Green et al 1997). However, considering the delayed onset of structural changes with all three bisphosphonates in our studies, it is likely that these early effects are due to functional changes rather than to acute tubular injury.…”

Section: Discussionsupporting

confidence: 58%

Acute Renal Effects of Intravenous Bisphosphonates in the Rat

Pfister

Atzpodien

Bohrmann

et al. 2005

Basic Clin Pharma Tox

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Bisphosphonates are potent osteoclast inhibitors that have been associated with renal toxicity following rapid intravenous administration of high doses, which was hypothesised to be due to precipitation of bisphosphonate aggregates or complexes in the kidney. Five studies were conducted in rats investigating the characteristics of bisphosphonate-related acute renal effects. These studies included single intravenous injections of the nitrogen-containing bisphosphonates (1) ibandronate (1-20 mg/kg), or (2) zoledronate (1-10 mg/kg); (3) a single nephrotoxic dose of the non-nitrogen-containing bisphosphonate, clodronate (2¿200 mg/kg intraperitoneal injection); (4) a single low dose of ibandronate (1 mg/kg); (5) a single high dose of zoledronate (10 mg/kg). Clinical biochemistry and kidney histopathology were performed 1 and/or 4 days after bisphosphonate dosing. The proximal convoluted tubules were the primary target for renal injury. Tubular degeneration and single cell necrosis of the these tubules were observed with all three bisphosphonates on the fourth, but not the first day after dosing. Differences between the bisphosphonates in the type and/or localisation of the lesions were apparent. Granular deposits in the lumen of distal tubules were apparent with the highest dose of zoledronate (10 mg/kg). However, intraluminal debris was proteinaceous with no evidence of any precipitation of bisphosphonate, or formation of aggregates or complexes in the kidney. Generally, biochemical parameters of renal safety and urinary enzymes did not differ significantly from controls. In summary, bisphosphonate-related renal changes did not appear to be due to the precipitation, aggregation or complexation of bisphosphonate, and biochemical parameters of renal safety did not reliably detect this renal injury.

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Section: Discussionsupporting

confidence: 58%

Acute Renal Effects of Intravenous Bisphosphonates in the Rat

Pfister

Atzpodien

Bohrmann

et al. 2005

Basic Clin Pharma Tox

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“…The nonacute, nonskeletal toxicity is usually manifested, as is the case with many phosphates and polyphosphate, first in the kidney (271,272). This occurs, however, only at doses substantially larger than those administered in humans.…”

Section: A Animal Toxicologymentioning

confidence: 99%

Bisphosphonates: Mechanisms of Action

1998

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“…This same process may be responsible for the podocyte abnormalities observed in pamidronate nephrotoxicity (Markowitz et al, 2001). The dose effect is critical; increased pamidronate dose has been associated with non‐linear excretion, increased accumulation in kidneys and proximal tubular damage in animal models (Cal & Daley‐Yates, 1999).…”

Section: Discussionmentioning

confidence: 99%

Nephrotic proteinuria associated with high‐dose pamidronate in multiple myeloma

et al. 2002

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Summary. Five patients receiving increased dose or frequency of pamidronate beyond the recommended dose (90 mg/monthly) exhibited nephrotic proteinuria (range 3AE96-24 g/24 h). On dose reduction or discontinuation, three of these patients showed decreased proteinuria to normal levels (< 1 g/24 h), and proteinuria decreased to 4AE5 g/24 h from a peak of 24 g/24 h in one patient. One patient on haemodialysis (hence not evaluable) had proteinuria of 2 g/24 h and elevated creatinine levels. One other patient continued to show elevated creatinine levels (272AE8 lmol/l). Renal biopsies obtained in two patients revealed focal segmental glomerulosclerosis.

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Disposition and nephrotoxicity of 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD), in rats and mice

Cited by 41 publications

References 24 publications

Acute Renal Effects of Intravenous Bisphosphonates in the Rat

Acute Renal Effects of Intravenous Bisphosphonates in the Rat

Bisphosphonates: Mechanisms of Action

Nephrotic proteinuria associated with high‐dose pamidronate in multiple myeloma

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