Metabolism and pharmacokinetics of pharmaceuticals in cats (Felix sylvestris catus) and implications for the risk assessment of feed additives and contaminants

Lautz, L.S.; Jeddi, Maryam Zare; Girolami, Flavia; Nebbia, Carlo; Dorne, Jean‐Lou

doi:10.1016/j.toxlet.2020.11.014

Cited by 51 publications

(65 citation statements)

References 121 publications

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“…At the proposed use levels for the different species, the lowest MOET is ≥ 158 (Table 5) and > 500 for cats (Court and Greenblatt, 1997; Lautz et al., 2021). Therefore, with respect to the exposure to the volatiles present in the additive (except perillaldehyde), no safety concern was identified for expressed mandarin oil, when used as a feed additive at the proposed use levels.…”

Section: Assessmentmentioning

confidence: 99%

Safety and efficacy of a feed additive consisting of expressed mandarin oil from the fruit peels of Citrus reticulata Blanco for use in all animal species (FEFANA asbl)

Additives¹,

Bampidis²,

Azimonti³

et al. 2021

EFS2

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Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed ( FEEDAP ) was asked to deliver a scientific opinion on the safety and efficacy of expressed mandarin oil from the fruit peels of Citrus reticulata Blanco, when used as a sensory additive (flavouring) in feed and water for drinking for all animal species. The FEEDAP Panel concluded that the essential oil under assessment is safe up to the maximum proposed use levels in complete feed of 15 mg/kg for poultry, 33 mg/kg for pigs, 30 mg/kg for ruminants, 40 mg/kg for horse, and 15 mg/kg for salmon and rabbit. The presence of perillaldehyde was identified as a source of potential concern. However, in target species fed citrus by‐products as part of daily feed the use of the expressed mandarin oil in feed was not expected to increase the exposure to perillaldehyde to a relevant extent (< 4%). For companion animals and ornamental fish not normally exposed to citrus by‐products, no conclusion can be drawn. The FEEDAP Panel considered that the use in water for drinking is safe provided that the total daily intake of the additive does not exceed the daily amount that is considered safe when consumed via feed. No concerns for consumer safety were identified following the use of the additive up to the maximum proposed use level in feed. The essential oil under assessment should be considered as irritant to skin, eyes and the respiratory tract, and as a skin sensitiser. The use of the additive in animal feed under the proposed conditions of use was not expected to pose a risk for the environment. Expressed mandarin oil was recognised to flavour food. Since its function in feed would be essentially the same as that in food, no further demonstration of efficacy was considered necessary.

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Section: Assessmentmentioning

confidence: 99%

Safety and efficacy of a feed additive consisting of expressed mandarin oil from the fruit peels of Citrus reticulata Blanco for use in all animal species (FEFANA asbl)

Additives¹,

Bampidis²,

Azimonti³

et al. 2021

EFS2

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“…Phase II metabolism mechanisms are often responsible for differences in elimination and are not usually tested during early screening programs [ 2 ]. Even though cats are considered poor at glucuronidation compared to other species due to a lack of two UGT enzymes (UGT1A6 and UGT1A9), Lautz et al described cats as having a “peculiar expression and activity” of phase II metabolism enzymes [ 35 , 36 ] because they have other UGT and Phase II enzymes that efficiently metabolize xenobiotics. For this reason, stability of EC1728 was assessed in each species with UDPGA, PAPS and GSH, the necessary co-factors for the main phase II metabolism mechanisms.…”

Section: Resultsmentioning

confidence: 99%

“…Fortunately, as indicated by the low IC 50′ s on the target enzyme, the potency can be very high making the compounds attractive as pharmaceuticals in spite of their challenging physical properties. A surprise in examining the piperidine structures such as EC1770 and AR9281, an sEH inhibitor previously administered in human clinical trials for hypertension [ 35 ], was that although these structures were very potent inhibitors of rodent and primate enzymes their potency fell off dramatically in other species, particularly the cat [ 23 ]. Thus, when EC1728 was selected as an Investigational New Animal Drug candidate for canine and equine use, we evaluated it for use in felines.…”

Section: Discussionmentioning

confidence: 99%

“…The most notable variability between species was between cats and dogs, with cats displaying faster clearance of EC1728 vs. dogs, and dogs demonstrating much slower clearance than would have been predicted by allometric scaling ( Figure 3 ). Cats are reported to metabolize compounds more slowly than other animals due to having lower levels of CYP450 enzymes, and lack of two glucuronidation (UGT1A6 and UGT1A9) and one ATP-binding cassette transporter (ABCG2) [ 5 , 34 , 35 ]. While faster metabolism typically represents less risk of toxicity, it makes identifying effective concentrations more challenging.…”

Section: Discussionmentioning

confidence: 99%

“…Based on this BDDCS classification, EC1728 would be highly absorbed but also influenced by transporters. There is limited information available on specific transporters in cats besides a lack of ATP-binding cassette G2 transporters [ 5 , 34 , 35 ]; however, based on the stability in vitro in liver microsomes and S9 fractions, a unique species-specific interaction with a transporter may explain the low oral bioavailability in cats and increased exposure in dogs. Due to the use of dogs as the preferred tox species in the development of human drugs, much more is known about the expression of dog transporters; but even in dogs, little is known about the functional role these changes play in the absorption or elimination of xenobiotics [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor, EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development

et al. 2021

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There are few novel therapeutic options available for companion animals, and medications rely heavily on repurposed drugs developed for other species. Considering the diversity of species and breeds in companion animal medicine, comprehensive PK exposures in the companion animal patient is often lacking. The purpose of this paper was to assess the pharmacokinetics after oral and intravenous dosing in domesticated animal species (dogs, cats, and horses) of a novel soluble epoxide hydrolase inhibitor, EC1728, being developed for the treatment of pain in animals. Results: Intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50% F) but lower in mice and cats (34 and 8%, respectively). Additionally, clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses. Efficacy with EC1728 has been demonstrated in mice, dogs, and horses, and despite the rapid clearance of EC1728 in cats, analgesic efficacy was demonstrated in an acute pain model after intravenous but not oral dosing. Conclusion: These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity.

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Evidence of a sudden increase in α‐chloralose poisoning in dogs and cats in the Netherlands between 2018 and 2021

et al. 2022

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Background After changes in European Union biocide legislation, the Dutch Poisons Information Center observed a strong increase in information requests concerning dogs and cats exposed to α‐chloralose. To investigate whether α‐chloralose‐based rodenticides are safe for non‐professional use, additional information regarding poisoning scenarios and clinical course was collected. Methods Veterinarians reporting α‐chloralose exposure over a 2.5‐year period were contacted by mail for follow‐up information concerning exposure scenario, product formulation, clinical course and treatment, and outcome. In total, information was collected for 96 dogs and 41 cats. Results Fifty‐three of 96 dogs and 17 of 19 cats known to have been exposed to α‐chloralose‐based rodenticides developed signs of central nervous system (CNS) depression or sensory‐induced CNS excitation. Mortality in dogs and cats following exposure was 1% and 18%, respectively. An additional 22 cats presented with clinical signs suggestive of α‐chloralose poisoning, with a mortality of 5%. Limitations Exposure to α‐chloralose was not confirmed by biochemical analyses. Conclusion Dogs and especially cats were at risk of poisoning from α‐chloralose. If criteria such as acute toxicity and risk of (secondary) poisoning are applied during the approval of α‐chloralose‐based rodenticides, similar to anticoagulant‐based rodenticides, it can be concluded that α‐chloralose is also not safe for non‐professional use.

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Metabolism and pharmacokinetics of pharmaceuticals in cats (Felix sylvestris catus) and implications for the risk assessment of feed additives and contaminants

Cited by 51 publications

References 121 publications

Safety and efficacy of a feed additive consisting of expressed mandarin oil from the fruit peels of Citrus reticulata Blanco for use in all animal species (FEFANA asbl)

Safety and efficacy of a feed additive consisting of expressed mandarin oil from the fruit peels of Citrus reticulata Blanco for use in all animal species (FEFANA asbl)

Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor, EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development

Evidence of a sudden increase in α‐chloralose poisoning in dogs and cats in the Netherlands between 2018 and 2021

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