OBJECTIVE
To determine the single-dose pharmacokinetics of clodronate disodium (CLO) in juvenile sheep and the plasma protein binding (PPB) of CLO in juvenile sheep and horses.
ANIMALS
11 juvenile crossbred sheep (252 ± 6 days) for the pharmacokinetic study. Three juvenile crossbred sheep (281 ± 4 days) and 3 juvenile Quarter Horses (599 ± 25 days) for PPB analysis.
METHODS
CLO concentrations were determined using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis from plasma samples obtained at 0, 0.5, 1, 3, 6, 12, 24, 48, and 72 hours after CLO administered IM at 0.6 mg/kg. PPB was determined using equine and ovine plasma in a single-use rapid equilibrium dialysis system.
RESULTS
The mean and range for maximum plasma concentration (Cmax: 5,596; 2,396–8,613 ng/mL), time of maximal concentration (Tmax: 0.5; 0.5–1.0 h), and area under the curve (AUCall: 12,831; 7,590–17,593 h X ng/mL) were similar to those previously reported in horses. PPB in sheep and horses was moderate to high, with unbound fractions of 26.1 ± 5.1% in sheep and 18.7 ± 7.5% in horses, showing less than a 1.4-fold difference.
CLINICAL RELEVANCE
The pharmacokinetic parameters and PPB of CLO in juvenile sheep were similar to those previously reported in horses. The results suggest that juvenile sheep can be utilized as an animal model for studying the potential risks and/or benefits of bisphosphonate use in juvenile horses.
Objective: To determine the effects of clodronate disodium (CLO) on control and recombinant equine interleukin-1β (IL-1β)-treated equine joint tissues. Study design: In vitro experimental study. Sample population: Cartilage explants, chondrocytes, and synoviocytes (n = 3 horses).Methods: Monolayer cultures of chondrocytes and synoviocytes from three horses were subjected to: control media (CON), 5 ng/ml CLO (C/low), 50 ng/ml CLO (C/med), 100 ng/ml CLO (C/high), with and without IL-1β, and 10 ng/ml IL-1β (IL) alone for 72 hours. Cartilage explants from three horses were subjected to CON, IL, C/low, and C/med with and without IL-1β for 72 hours. Culture media was analyzed for prostaglandin-E 2 (PGE 2 ), interleukin-6 (IL-6), and nitric oxide (NO). Explant media was analyzed for glycosaminoglycan (GAG) content and NO. At 72 hours, explant and monolayer culture viability were assessed, and explant GAG content was measured.Results: IL-1β treatment resulted in higher media concentrations of GAG, NO, PGE 2 , and IL-6 compared to the CON treatment (p < .05), demonstrating a catabolic effect of IL-1β on explants and monolayer cultures. CLO treatments did not increase media concentrations of GAG, NO, PGE 2 , or IL-6 compared to CON, indicating no cytotoxic effect. Nevertheless, CLO treatments administered to IL-1β-treated monolayer cultures and explants did not significantly reduce the inflammatory response regardless of concentration.
Conclusion:CLO did not demonstrate cytotoxic nor cytoprotective effects in normal and IL-1β-stimulated chondrocytes, synoviocytes or explants in culture.Clinical significance: This study does not support the use of CLO as an antiinflammatory treatment. Further research is necessary to confirm any antiinflammatory effects of CLO on joint tissues.
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