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Asian Gyps vulture species are gradually recovering from the devastating effect of diclofenac being present in contaminated carcasses. This drug was responsible for the death of over 10 million vultures in India, Nepal and Pakistan. To prevent the extinction of vultures, meloxicam was introduced after the ban of veterinary diclofenac. Meloxicam's safety in vultures was attributed to its short elimination half-life in contrast with diclofenac. The reason for the rapid elimination of meloxicam is yet to be explained. The aim of this study was to evaluate the role of biotransformation in the elimination of meloxicam. Six Cape griffon vultures (Gyps coprotheres) were treated with 2 mg/kg meloxicam intramuscularly for faecal and plasma quantification of meloxicam concentration over time. In the plasma meloxicam was characterised by a half-life, mean residence time, clearance and volume of distribution at steady state of 0.37 ± 0.10 h, 0.90 ± 0.12 h, 0.02 ± 0.00 l/h kg and 0.02 ± 0.00 l/kg respectively (presented as geometric mean). Over the 24 h monitoring period, the total non-metabolised meloxicam in the faeces was 1.35 ± 0.71% of the total concentration in the plasma. Based on the short meloxicam elimination half-life and low cumulative concentration of total faecal meloxicam over a period in excess of 10 half-lives, this study indicates that Cape griffon vultures are efficient metaboliser of meloxicam, which is suggestive of different set of cytochrome enzymes being involved in the metabolism to that for diclofenac in this species. Identification of orthologous human CYP2C9 and CYP3A4 enzyme families in vultures will be an important further step in explaining the differences in the metabolic pathway(s) of meloxicam and diclofenac for the species., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Diclofenac, a non-steroidal anti-inflammatory pharmaceutical agent was responsible for the death of millions of Gyps vulture's in the Indian sub-region with the safety of the other non-steroidal anti-inflammatory drugs (NSAIDs) being questionable. With preclinical safety testing not well established for avian species unlike for mammalian and environmental toxicity, we ask the question if a preclinical model could have predicted the toxic effect of the drug. For this study, we test an Organisation for Economic Co-operation and Development (OECD) guideline 223 for assessing the acute toxic potential of pesticides in birds by exposing three avian species to the drug. Exposed Japanese quails (Coturnix japonica) and Muscovy ducks (Cairina moschata) demonstrated clinical signs and pathology similar to those previously reported in vultures viz. hyperuricemia, depression, death, visceral gout and nephrosis. However, exposed domestic pigeons (Columba livia domestica) were insensitive. Following a pharmacokinetic analysis, the drug was well absorbed and distributed in the pigeons with a half-life below 6 h. A toxicokinetic evaluation in quails showed poisoning was due to metabolic constraint, with a half-life and mean residence time above 6 h and 8 h respectively resulting in death. Toxicity seen in the ducks was however not related to metabolic constraint but hyperuricemia as metabolism was rapid [half-life (1-2 h) and mean residence time (2-3 h)] irrespective of survival or death. Despite succumbing to diclofenac, the established oral median lethal dose (LD 50 ) of 405.42 mg/kg and 189.92 mg/kg in Japanese quails and Muscovy ducks respectively from this study were substantially higher than those reported for Gyps vultures (0.098 mg/kg) which is as a result of the rapid elimination of the drug from the body in the former species. More importantly, it suggests that these species are not suitable as surrogates for non-steroidal anti-inflammatory drug toxicity testing and that the toxicity of diclofenac in vultures is idiosyncratic most likely as a result of species specific metabolism., (Copyright © 2018 Elsevier B.V. All rights reserved.)