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The unintended environmental exposure of vultures to diclofenac has resulted in the deaths of millions of old-world vultures on the Asian subcontinent. While toxicity has been since associated with a long half-life of elimination and zero order metabolism, the actual constraint in biotransformation is yet to be clarified. For this study we evaluated if the evident zero order metabolism could be due to defects in the CYP2C9/2C19 enzyme system. For this, using whole genome sequencing and de-novo transcriptome alignment, the vulture CYP2C19 open reading frame was identified through Splign analysis. The result sequence analysis revealed the presence of a premature stop codon on intron 7 of the identified open reading frame. Even if the stop codon was not present, amino acid residue analysis tended to suggest that the enzyme would be lower in activity than the equivalent human enzyme, with differences present at sites 105, 286 and 289. The defect was also conserved across the eight non-related vultures tested. From these results, we conclude that the sensitivity of the old-world vultures to diclofenac is due to the non-expression of a viable CYP2C19 enzyme system. This is not too dissimilar to the effects seen in certain people with a similar defective enzyme., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 drug (NSAID) was responsible for the death of millions of vultures on the Asian subcontinent, following the consumption of diclofenac contaminated carcasses. The aim of this research was to establish if liver slices could serve as an alternate means of predicting the toxicity of NSAIDs in Gyps vultures. The Cape vulture liver slices was prepared and incubated with four NSAIDs for 6 h. A percent clearance of 1.0 ± 0.253, 0.58 ± 0.153, 0.961 ± 0.312 and 1.242 ± 0.406 (%/h*g) was attained for diclofenac, carprofen, ketoprofen and meloxicam respectively. Both meloxicam and diclofenac exerted toxic effects on the hepatic cells. Protein content indicated that the vulture tissue had lower enzyme levels than expected for an animal of its size. The poor distinction between the ex vivo hepatic percent clearance of meloxicam and diclofenac indicates that liver slices is not an ideal model to investigate NSAIDs toxicity in Cape vulture., (Copyright © 2018 Elsevier B.V. All rights reserved.)