The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

Naidoo, Vinny; Venter, Linda; Wolter, Kerri; Taggart, Mark A.; Cuthbert, Richard

doi:10.1007/s00204-010-0521-0

Cited by 48 publications

(37 citation statements)

References 23 publications

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“…This once again supported previous findings that toxicity is related to zero-order metabolism. In addition, the increase in the AUC last and C max also indicated that toxicity resulted in saturation of presystemic elimination pathways [64].…”

Section: In Vivo Approaches In Studying Comparative Metabolismmentioning

confidence: 99%

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

Hutchinson

Madden

Naidoo

et al. 2014

Phil. Trans. R. Soc. B

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Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET) of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions (which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conjugation with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human–fish plasma model provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibuprofen and propranolol) in freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with low metabolic competency may exhibit zero-order metabolic (pharmacokinetic) profiles and thus high API toxicity, as in the case of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism (suggesting P450 Phase I enzyme system or Phase II glucuronidation deficiencies). While all aspects of ADMET are important in toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a central part of environmental risk assessment.

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Section: In Vivo Approaches In Studying Comparative Metabolismmentioning

confidence: 99%

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

Hutchinson

Madden

Naidoo

et al. 2014

Phil. Trans. R. Soc. B

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show abstract

“…While models are also available for uptake and metabolism, understanding inter- and intraspecies variation is fundamental to predicting toxicity. Experiments by Vinny Naidoo (University of Pretoria) have shown that Gyps and other vulture species have an unusual metabolism with respect to NSAIDs [16]; they are suggested to be CYP 2C9 deficient or diminished, as are cats, which are also highly sensitive to NSAIDs and so may provide a pharmacokinetic model for vultures.…”

Section: Behaviour Of Pharmaceuticalsmentioning

confidence: 99%

Assessing the exposure risk and impacts of pharmaceuticals in the environment on individuals and ecosystems

et al. 2013

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The use of human and veterinary pharmaceuticals is increasing. Over the past decade, there has been a proliferation of research into potential environmental impacts of pharmaceuticals in the environment. A Royal Society-supported seminar brought together experts from diverse scientific fields to discuss the risks posed by pharmaceuticals to wildlife. Recent analytical advances have revealed that pharmaceuticals are entering habitats via water, sewage, manure and animal carcases, and dispersing through food chains. Pharmaceuticals are designed to alter physiology at low doses and so can be particularly potent contaminants. The near extinction of Asian vultures following exposure to diclofenac is the key example where exposure to a pharmaceutical caused a population-level impact on non-target wildlife. However, more subtle changes to behaviour and physiology are rarely studied and poorly understood. Grand challenges for the future include developing more realistic exposure assessments for wildlife, assessing the impacts of mixtures of pharmaceuticals in combination with other environmental stressors and estimating the risks from pharmaceutical manufacturing and usage in developing countries. We concluded that an integration of diverse approaches is required to predict ‘unexpected’ risks; specifically, ecologically relevant, often long-term and non-lethal, consequences of pharmaceuticals in the environment for wildlife and ecosystems.

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“…Generally speaking, far more information is urgently needed regarding NSAIDs known or suspected to cause gout-related mortality (e.g. carprofen, ibuprofen, ketoprofen, flunixin, phenylbutazone) [112][113][114], no less so now that diclofenac has been registered for veterinary use in some parts of Europe, especially Spain. This will entail assessing the disposition of these agents in a relevant suite of agricultural animals, conducting safety trials with vultures (or a vulture cell line) and actively monitoring for residue levels in livestock carcasses.…”

Section: The Situation In the European Unionmentioning

confidence: 99%

Merging Wildlife and Environmental Monitoring Approaches with Forensic Principles: Application of Unconventional and Non-Invasive Sampling in Eco- Pharmacovigilance

Richards¹

2014

J Forensic Res

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Pharmaceutical residues in the environment have the potential to harm wildlife. A population's fragility or an animal's secretive nature may preclude capture and the use of invasive/destructive sampling techniques that are typically used in a risk assessment. Conventionally favoured matrices gathered opportunistically from carcasses have a finite lifespan, thereby limiting the detection window. This multidisciplinary paper aims to promote the use of non-invasive approaches and optimize use of even the most degraded carcasses. We highlight a selection of promising alternative, unconventional and underutilized sample types that could be applied in environmental monitoring efforts and wildlife forensic investigations. With a focus on non-steroidal anti-inflammatory drugs (NSAIDs), now under increasing scrutiny in the freshwater and terrestrial environment, we first illustrate current sampling practices and gaps in knowledge by summarizing exposure of: 1) aquatic organisms to urban effluent discharged into waterways, and, 2) scavenging species to veterinary residues in livestock and other carrion. We then consider the merits and limitations of a range of alternative environmentally robust sample options that offer a broader detection interval for NSAIDs, with emphasis on hair, wool and feathers. The viability of eyes/ocular material, bone matter, fecal matter, injection sites, ingesta/pellets and scavenging/coprophagous insects are also discussed.

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The toxicokinetics of ketoprofen in Gyps coprotheres: toxicity due to zero-order metabolism

Cited by 48 publications

References 23 publications

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

Assessing the exposure risk and impacts of pharmaceuticals in the environment on individuals and ecosystems

Merging Wildlife and Environmental Monitoring Approaches with Forensic Principles: Application of Unconventional and Non-Invasive Sampling in Eco- Pharmacovigilance

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