Pharmacokinetics of carprofen in anaesthetized pigs: a preliminary study

Coşkun

Vet Pharm & Therapeutics

et al. 2022

The aim of this study was to determine the pharmacokinetics of carprofen following single and repeated intravenous (IV) administrations at 1.4 and 4 mg/kg doses in sheep. The study was carried out on twelve sheep in two experiments as single‐ and multiple‐dose pharmacokinetics. In experiment 1, carprofen was administered via IV at single doses of 1.4 (n = 6) and 4 mg/kg (n = 6) in a randomized parallel design. In experiment 2, the same dose groups in experiment 1 following the 21‐day washout period received intravenously carprofen every 24 h for 5 days. Plasma concentrations were measured using high‐performance liquid chromatography–UV and analyzed by a two‐compartment open model. After the single administration of 1.4 mg/kg dose, the t1/2α, t1/2el, MRT, ClT, Vdss, and AUC were 0.62 h, 27.57 h, 38.78 h, 2.72 ml/h/kg, 105.26 ml/kg, and 515.12 h*μg/ml, respectively. Carprofen at a single dose of 4 mg/kg showed prolonged t1/2el and MRT, and increased Vdss. On day 5 after the repeated administration of the 1.4 mg/kg dose, the t1/2α, t1/2el, MRT, ClT, Vdss, and AUC were 1.12 h, 57.48 h, 82.18 h, 0.55 ml/h/kg, 45.43 ml/kg, and 2532 h*μg/ml, respectively. Carprofen at a repeated dose of 4 mg/kg showed increased ClT and Vdss and decreased AUC/dose. Although the long t1/2ʎz in single and multiple IV dose studies suggest the possibility of its effective use, the IV route may not be practical in sheep. Therefore, oral and subcutaneous routes of carprofen in sheep would be more valuable in clinical settings.

Section: Discussionsupporting

confidence: 88%

Pharmacokinetics of carprofen following single and repeated intravenous administrations of different doses in sheep

Coşkun

Vet Pharm & Therapeutics

et al. 2022

“…Half-life values of our study were longer than those reported by Bošnjak M. et al [ 32 ], after IV administration at the same dose (t 1/2 β = 17.31 h). These differences could be due to the sampling schedules applied during the terminal phase, to which non-compartmental analysis is very sensitive.…”

Section: Discussioncontrasting

confidence: 65%

“…As reported by Bošnjak M. et al [ 32 ], the CP disposition was best described by a two-compartment model with first-order elimination. First-order kinetics described the absorption process after IM administration as occurred after oral administration [ 32 ].…”

Section: Discussionmentioning

confidence: 92%

“…Once given intravenously, CP rapidly achieved the pseudo-steady-state equilibrium, with a very long terminal phase accounting for most of the area under the plasma concentration–time profile. Among all the animal species in which the CP pharmacokinetics has been studied, swine shows the longest half-life values (t 1/2 λz IV = 36.34 ± 7.88 h, t 1/2 λz IM = 29.73 ± 5.56 h) [ 32 ] followed by humans [ 27 ] (t 1/2 λz IV = 9.91 ± 0.79 h, t 1/2 λzpo = 10.97 ± 1.40 h, t 1/2 λzpo = 16.01 ± 2.82 h) and horses [ 19 ] (11.35 ± 2.21 h).…”

Section: Discussionmentioning

confidence: 99%

“…The swine model has been used in pharmacokinetic (PK) studies of different drugs to further predict human PK through allometric models. Numerous CP pharmacokinetic studies have been conducted in various species: horses [ 18 , 19 ], donkeys [ 20 ], calves [ 21 , 22 ], sheep [ 23 ], rabbits [ 24 , 25 ], vultures [ 26 ], humans [ 27 ], dogs [ 28 , 29 ] and cats [ 30 , 31 ]; however, very few CP PK studies have been published in swine [ 32 ], probably because its use in this specie is uncommon. Moreover, CP have never been administered by the intramuscular route in this species.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Swine as the Animal Model for Testing New Formulations of Anti-Inflammatory Drugs: Carprofen Pharmacokinetics and Bioavailability of the Intramuscular Route

et al. 2022

Carprofen (CP) is a non-steroidal anti-inflammatory drug (NSAID) frequently used to treat respiratory diseases in numerous small animals, but also in large species. CP is a formidable candidate for further therapeutic research of human inflammatory diseases using the pig as an animal model. However, CP administration in swine is very uncommon and respective pharmacokinetics/bioavailability studies are scarce. A simultaneous population pharmacokinetic analysis after CP intravenous and intramuscular administrations in pigs has shown high extent and rate of absorption and a similar distribution profile with respect to man and other mammals. However, clearance and half-life values found in swine suggest a slower elimination process than that observed in man and some other animal species. Although not reported in other species, liver and kidney concentrations achieved at 48 h post-intramuscular administration in pigs were ten times lower than those found in plasma. Simulations pointed to 4 mg/kg every 24 h as the best dosage regimen to achieve similar therapeutic levels to those observed in other animal species. All these findings support the use of pig as an animal model to study the anti-inflammatory effects of CP in humans.

Loss of ZBED6 Protects Against Sepsis‐Induced Muscle Atrophy by Upregulating DOCK3‐Mediated RAC1/PI3K/AKT Signaling Pathway in Pigs

Liu

Pan

et al. 2023

Advanced Science

Sepsis‐induced muscle atrophy often increases morbidity and mortality in intensive care unit (ICU) patients, yet neither therapeutic target nor optimal animal model is available for this disease. Here, by modifying the surgical strategy of cecal ligation and puncture (CLP), a novel sepsis pig model is created that for the first time recapitulates the whole course of sepsis in humans. With this model and sepsis patients, increased levels of the transcription factor zinc finger BED‐type containing 6 (ZBED6) in skeletal muscle are shown. Protection against sepsis‐induced muscle wasting in ZBED6‐deficient pigs is further demonstrated. Mechanistically, integrated analysis of RNA‐seq and ChIP‐seq reveals dedicator of cytokinesis 3 (DOCK3) as the direct target of ZBED6. In septic ZBED6‐deficient pigs, DOCK3 expression is increased in skeletal muscle and myocytes, activating the RAC1/PI3K/AKT pathway and protecting against sepsis‐induced muscle wasting. Conversely, opposite gene expression patterns and exacerbated muscle wasting are observed in septic ZBED6‐overexpressing myotubes. Notably, sepsis patients show increased ZBED6 expression along with reduced DOCK3 and downregulated RAC1/PI3K/AKT pathway. These findings suggest that ZBED6 is a potential therapeutic target for sepsis‐induced muscle atrophy, and the established sepsis pig model is a valuable tool for understanding sepsis pathogenesis and developing its therapeutics.