Could the environmental toxicity of diclofenac in vultures been predictable if preclinical testing methodology were applied?

Abstract

Text: 4,324 Reference list: 824 HIGHLIGHTS  Obtained pharmacokinetic data could not always associate metabolic constraint as the major cause of poisoning.  The uric acid plasma buffering capacity of a species could be used as a measure of diclofenac's safety. 2  Toxicity of diclofenac in vultures is idiosyncratic as the oral LD50 is substantially lower than those of other model species.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) and their Effect on Old World Vultures: A Scoping Review

“…Furthermore, mortality and signs of toxicity have also been reported in vultures and other avian species after exposure to other NSAIDs such as flunixin and ketoprofen (e.g., Naidoo et al 2010b, Kapadiya et al 2015, Zorrilla et al 2015. Other NSAIDs such as carprofen and nimesulide may also pose a risk to vultures, but there is still a lack of compelling evidence, and some of the currently available data from other avian species cannot be fully extrapolated to vultures given their very different physiology (Cuthbert et al 2007a, Hassan et al 2018). Meloxicam appears to be the safest NSAID thus far for vultures, but research is still limited (Adawaren et al 2019).…”

Diclofenac Sensitivity to Vultures’ Death and Environmental Pharmacology

“…19,20 Uptake and Biological Effects of Environmentally Relevant Concentrations of the Nonsteroidal Anti-inflammatory Pharmaceutical Diclofenac in Rainbow Trout (Oncorhynchus mykiss) is thoroughly studied by Mehinto. 21 Preclinical safety testing has not been well established for avian species unlike for mammalian and environmental toxicity, Hasan Izet al 22 put forward a question if there was a preclinical model that could have predicted the toxic effect of the drug. To test the acute toxic potential of pesticides in birds under Organization for Economic Cooperation and Development (OECD) guidelines (guideline 223), three avian species were exposed to the drug.…”

“…More importantly, it suggests that these species are not suitable as surrogates for nonsteroidal anti-inflammatory drug toxicity testing and that the toxicity of diclofenac in vultures is idiosyncratic most likely as a result of species specific metabolism. 22 Captive Vulture Breeding Program Captive breeding program is the most important tool in the fight against the extinction of vultures. Three captive breeding centers housing the three species under impending extinction have been built across India.…”

Effect of cytochrome P450 inhibition on toxicity of diclofenac in chickens: Unravelling toxicity in Gyps vultures

“…In comparison, the LD 50 in the domestic chicken ( Gallus gallus domesticus ) was 9.8 mg/kg (Naidoo et al 2007 ) and as high as 616 mg/kg in the pigeon ( Columba livia domestica ) (Hassan et al 2018 ). The difference in LD 50 also appeared to be correlated with the pharmacokinetic parameter T 1/2 or half-life of elimination, suggesting deficient metabolism as a cause of increased sensitivity.…”