Validating the domestic fowl as a model to investigate the pathophysiology of diclofenac in Gyps vultures

Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction

“…This is in support of the findings of (Ng et al, 2006) and (Ng et al, 2008) especially with the toxicity being associated with a 200% increase in ROS production. For both diclofenac and meloxicam, the avian primary cells were much more susceptible than the mammalian cultures as reported by Ng et al (2008) (> 100 fold, based on the concentration reported to kill 40% of the cell culture), and was in line with the lower median lethal dose (LD 50 ) reported for the chicken (Naidoo et al, 2007). Unlike Ng et al (2008), MLX was toxic to the avian cells at much lower concentrations than DF.…”

“…chicken toxicity was not related to long-term exposure. In the case of MLX no vulture was exposed to plasma concentrations above 5 μg/ml for more than 0.5 h (Naidoo et al, 2007 andNaidoo et al, 2008a). When cultures were exposed to DF and MLX for only 2 h, no toxicity was evident for both MLX while DF remained significantly toxic (p < 0.05 for all concentrations) thereby indicating an alternate or additional mechanism behind toxicity.…”

“…For the toxicity and transporter assay, the concentrations tested are based on the extrapolated LD 50 of the diclofenac/meloxicam in the chicken and vulture, depending on which cells were used (Naidoo et al, 2007 andNaidoo et al, 2008a).…”

“…The latter is plausible as similar PAH and MRP channels are involved with UA excretion in the chicken (birds do not reabsorbed UA) (Khamdang et al, 2002, Rafey et al, 2003, Dudas et al, 2005, Enomoto and Endou, 2005and Mount et al, 2006. In addition both diclofenac and phenylbutazone have been shown to induce uricemia in the chicken (Berger et al, 1960 andNaidoo et al, 2007).…”

“…In addition, we propose that toxicity may be related to drug's ability to influence UA excretion as studies by Naidoo et al (2007) demonstrated that the main clinical signs of depression, following exposure to diclofenac, was a direct result of the marked increase in plasma uric acid concentrations. Since the mammalian kidney is influenced by the uricosuric effects of DF and MLX through the inhibition of the epithelial cell's basolateral UA-excreting organic anionic transporters (OATs) (also referred to as a PAH transporter), multi-drug resistance protein (MRP) and the apical UA reabsorptive channel known as URAT1, it is possible that a similar effect occurs in the vulture.…”