The use of toxicokinetics and exposure studies to show that carprofen in cattle tissue could lead to secondary toxicity and death in wild vultures

Veterinary medicines can be extremely damaging to the environment, as seen with the catastrophic declines in Gyps vulture in South Asia due to their secondary exposure to diclofenac in their primary food source. Not surprisingly, concern has been raised over other similar drugs. In this study, we evaluate the toxicity of carprofen to the Gyps vulture clade through plasma pharmacokinetics evaluations in Bos taurus cattle (their food source) and Gyps africanus (a validated model species); tissue residues in cattle; and the effect of carprofen as a secondary toxicant as both tissue-bound residue or pure drug at levels expected in cattle tissues. Carprofen residues were highest in cattle kidney (7.72 ± 2.38 mg/kg) and injection site muscle (289.05 ± 98.96 mg/kg of dimension of 5 × 5 × 5 cm). Vultures exposed to carprofen as residues in the kidney tissue or pure drug equivalents showed no toxic signs. When exposed to average injection site concentrations (64 mg/kg) one of two birds died with evidence of severe renal and liver damage. Toxicokinetic analysis revealed a prolonged drug half-life of 37.75 h in the dead bird as opposed to 13.99 ± 5.61 h from healthy birds dosed intravenously at 5 mg/kg. While carprofen may generally be harmless to Gyps vultures, its high levels at the injection site in treated cattle can result in lethal exposure in foraging vultures, due to relative small area of tissue it is found therein. We thus suggest that carprofen not be used in domesticated ungulates in areas where carcasses are accessible or provided to vultures at supplementary feeding sites.The Royal Society for the Protection of Birds and the Chester Zoo.http://www.elsevier.com/locate/chemosphere2019-01-01hj2018Paraclinical Science

Metabolism of aceclofenac in cattle to vulture-killing diclofenac

The non-steroidal anti-inflammatory drug (NSAID) diclofenac is highly toxic to Gyps vultures and its recent widespread use in South Asia caused catastrophic declines in at least three scavenging raptors. The manufacture of veterinary formulations of diclofenac has since been banned across the region with mixed success. However, at least 12 other NSAIDs are available for veterinary use in South Asia. Aceclofenac is one of these compounds and it is known to metabolise into diclofenac in some mammal species. The metabolic pathway of aceclofenac in cattle, the primary food of vultures in South Asia, is unknown. In this study, we give six cattle the recommended dose of aceclofenac (2 mg/kg), collect blood along a time series and undertake a pharmacokinetic analysis of aceclofenac and diclofenac-metabolites in their plasma using liquid chromatography with mass spectrometry. We found that nearly all of the aceclofenac administered to the cattle was very rapidly metabolised into diclofenac. Therefore, treating livestock with pure diclofenac or aceclofenac poses the same risk to vultures. This fact, coupled with the risk that aceclofenac may replace diclofenac in the veterinary market, fortifies the need for an immediate ban on all aceclofenac formulations that can be used to treat livestock. Without such a ban, the recovery of vultures across South Asia will not be successful.This study was largely funded by the RSPB Centre for Conversation Science. In addition, SAC Consulting: Veterinary Services receives funding from the Scottish Government through the Veterinary and Advisory Services (VAS) programme.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1523-17392017-10-31hb2016Paraclinical Science