Journal of veterinary pharmacology and therapeutics最新文献

Diazepam (DZP) residues in aquaculture environments pose a serious threat to food safety. To investigate the pharmacokinetics and residue elimination patterns of DZP using zebrafish as a model organism, a pharmacokinetic study, zebrafish were exposed to 1 mg/L DZP via bath for 24 h. DZP was metabolized to nordiazepam (NDZP), oxazepam (OZP), and temazepam (TZP). Non-compartmental analysis yielded the following pharmacokinetic parameters: T_1/2 = 4.25-11.78 h; MRT = 3.52-7 h; AUC = 34.51-4222.69 h·μg/kg; Vd = 1.16-6.15 L/kg; CL = 0.14-0.57 L/h/kg. The results indicate that DZP and its metabolites are rapidly absorbed and widely distributed in zebrafish, but eliminated slowly. For the residue elimination study, OZP fell below the LOD (0.05 μg/kg) after 40 days; NDZP and TZP were undetectable after 60 days. DZP persisted at 0.54 ± 0.2 μg/kg on day 150, confirming exceptionally slow elimination. The findings are expected to fill a critical data gap concerning the pharmacokinetics and residue elimination of DZP in zebrafish. These findings provide a framework for extending the results to similar rare edible small fish, thereby aiding in food safety assessment and risk management.

Drug leaching from medicated feeds into water reduces the available drug for absorption in the gut and causes negative effects in environments. The objectives of this study were to evaluate various top-coating materials in reducing the leaching of florfenicol (FF) from shrimp medicated feed and to determine the drug concentrations in the body of Pacific white shrimp (Litopenaeus vannamei) fed medicated feed top-coated with tuna oil, chitosan, pectin, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose sodium (CMC), and ethylcellulose (EC). FF concentrations that leached from the medicated feeds into water were analyzed using the HPLC method. Drug concentrations in the hemolymph and muscle of shrimp following oral administration were also analyzed. The results revealed that chitosan was the most effective material in reducing drug leaching, with only 27.8% leaching rate at 120 min. Tuna oil had the highest leaching rate (71.6%). Shrimp fed chitosan-coated medicated feed had significantly higher FF levels in hemolymph (2.04 μg/mL) and muscle (0.92 μg/g) than the other coating material groups. The tuna oil group had the lowest drug levels (0.20 μg/mL and 0.34 μg/g, respectively). These findings indicate that chitosan is the most effective in minimizing drug leaching and also exhibits the highest drug absorption in shrimp.

The ATP-binding cassette transporter MDR1 P-glycoprotein (syn. ABCB1) is an efflux carrier at the cell membrane that regulates drug absorption, distribution, and elimination. At the blood-brain barrier, MDR1 restricts brain entry of potentially neurotoxic drugs, such as ivermectin. In dogs and cats, MDR1 (syn. ABCB1) gene deletion mutations exist that have been associated with increased neurological toxicity after ivermectin treatment. The present study found an allelic frequency of 0.625% for the MDR1 mutation in 800 cats from Germany. In addition, the canine and feline mutant and wild-type MDR1 proteins were expressed in HEK293 and MDCKII cells, and transport experiments were performed with the fluorescent MDR1 probe substrate rhodamine 123. In both cell lines, significant MDR1-mediated rhodamine 123 efflux was identified for the wild-type MDR1 proteins, but not for the mutant MDR1 proteins, confirming a complete loss-of-function phenotype due to MDR1 gene mutation. Competitive in vitro studies showed inhibition of both wild-type MDR1 carriers with the reference MDR1 inhibitors verapamil (IC₅₀ = 5-9 μM), PSC833 (IC₅₀ = 1-2 μM), and tariquidar (IC₅₀ = 0.1-0.2 μM), as well as with the antiparasitic drugs ivermectin (IC₅₀ = 3-4 μM), eprinomectin (IC₅₀ = 3-4 μM), moxidectin (IC₅₀ = 8-21 μM), selamectin (IC₅₀ = 10-22 μM), lotilaner (IC₅₀ = 11-23 μM), and sarolaner (IC₅₀ = 30-57 μM), clearly demonstrating multi-drug interactions with the MDR1 carriers from both species.

Accurate prediction of drug depletion half-lives plays a pivotal role in determining extralabel withdrawal intervals and ensuring the safety of food products derived from livestock. In this study, we employed machine learning (ML)-based quantitative structure-activity relationship (QSAR) models and an innovative chemical language model-based QSAR approach (ImprovedChemBERTa) to estimate plasma and tissue half-lives of drugs administered to cattle through different administration routes. Utilizing a dataset from the Food Animal Residue Avoidance Databank (FARAD) Comparative Pharmacokinetic Database, we developed one "descriptor-free" ImprovedChemBERTa model and 20 ML-QSAR models, integrating four different ML algorithms with five categories of molecular descriptors. Among ML-QSAR approaches, the deep neural network (DNN) method employing all descriptors achieved the highest predictive accuracy (test R²: 0.37). In contrast, the ImprovedChemBERTa model significantly outperformed traditional methods, reaching a test R² of 0.69, underscoring the superior capability and transfer learning potential of chemical language models. Our findings highlight the effectiveness of chemical language model-based QSAR strategies, which directly process raw chemical representations without requiring explicitly generated molecular descriptors. Overall, this work provides a robust foundation for advancing tissue-specific QSAR modeling in major food-animal species and supports global efforts toward enhanced food safety regulation.

Captive-reared kiwi (Apteryx spp.) chicks commonly suffer from coccidiosis, a parasitic disease that can cause morbidity and mortality in young immune-naive birds. Disease is currently managed in captivity through a combination of preventative husbandry practices and therapeutic treatment with the coccidiocide toltrazuril, for which no safety or pharmacokinetic data is available for kiwi. In this study we attempted to determine the pharmacokinetics of synthetic triazine anticoccidials, toltrazuril and diclazuril, in healthy three-to-four-week-old North Island brown kiwi (Apteryx mantelli) chicks. Birds were given a single oral dose of toltrazuril (25 mg/kg.bw; n = 6) or diclazuril (5 mg/kg.bw; n = 6), and closely monitored for adverse reactions. Serial blood samples were analysed via liquid chromatography-mass spectrometry (LC-MS) to determine the pharmacokinetics of both drugs, including the active metabolite of toltrazuril, toltrazuril sulphone. Pharmacokinetics were ascertained for both drugs in kiwi chicks. The mean (standard deviation) C_max of diclazuril in plasma was 539.48 ± 169.63 ng/mL with a T_max of 11.33 ± 1.63 h, while the C_max for toltrazuril was 5622.16 ± 1997.52 ng/mL with a T_max of 11.33 ± 1.63 h and C_max of toltrazuril sulphone 3623.01 ± 1085.71 ng/mL with a T_max of 96 ± 26.29 h. Mild changes to some biochemical parameters were observed, most notably elevations in uric acid in some toltrazuril-treated birds; however no remarkable clinical changes were observed in any chicks dosed with the drugs trialled.

Pharmacokinetics (PK) of intramuscular (IM) and subcutaneous (SC) ketamine in horses has not been described. This study aimed to evaluate the PK and safety of ketamine and its metabolites after a single SC or IM administration. In Phase 1, two horses received 0.5 or 1 mg/kg of ketamine via SC and IM routes. In Phase 2, eight horses received 0.5 mg/kg IM. Plasma or serum concentrations of ketamine and major metabolites were determined by a validated liquid chromatography-mass spectrometry method at baseline and selected intervals post-administration. Subcutaneous administration resulted in extremely low concentrations (< 5 ng/mL). Phase 2 focused only on IM administration. Median peak serum ketamine concentrations after IM administration were 20.9 ng/mL (IQR 15.2-35.9) with a time to peak drug concentration of 1.4 h (IQR = 0.8-1.9 h) and terminal half-life of 1.8 h (IQR = 1.3-2.6 h). No changes in physical examination or laboratory parameters were observed. Ketamine metabolites were detected within 5 min after IM administration, with norketamine as the predominant metabolite. A single IM administration in healthy horses resulted in rapid absorption and variable inter-individual concentrations without adverse effects. Future studies should investigate repeated IM dosing and determine therapeutic plasma concentrations in horses.

The objective of this study was to determine and compare the pharmacokinetics of oral firocoxib, oral meloxicam, and transdermal flunixin (TD) in 44 adult, male castrated, crossbred goats. Pharmacokinetic (PK) analysis was performed for each goat in each phase using non-compartmental methods with descriptive statistics reported. Mean plasma half-life (T_1/2 (h)) for oral (PO) administration of firocoxib at varying dosages in meat type castrated goats was reported at 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg at 9.1 (range 6.9-13.4), 10.2 (range 6.4-14.7) and 9.2 (range 6.8-12.8), respectively. For oral meloxicam, mean plasma T_1/2 at doses of 1.0 mg/kg, 2.0 mg/kg, and 3.0 mg/kg were 13.3 (range: 10.1-22.3), 13.1 (range: 12-24), and 11.7 (range: 8.3-20.5) hours, respectively. Transdermal flunixin showed mean plasma T_1/2 of 16.5 (range: 10.7-62) at 3.3 mg/kg, 22.0 (range: 16.6-67.4) at 4.2 mg/kg, and 17.8 (range: 7.4-56.3) at 5.0 mg/kg. These results highlight significant variability in drug disposition and suggest that further research is warranted to optimize dosing regimens for oral firocoxib, oral meloxicam, and transdermal flunixin in goats.

Buserelin acetate, a synthetic analog of gonadotropin-releasing hormone (GnRH), is used to induce ovulation and enable fixed-time artificial insemination (FTAI) in swine. Evaluating the pharmacokinetics of buserelin acetate is crucial for optimizing its application in precisely controlling ovulation timing and enhancing the effectiveness of FTAI in pigs. This study investigates the pharmacokinetics of buserelin acetate following intramuscular administration in gilts. Ten healthy prepuberty gilts (Landrace × Yorkshire × Duroc) with an average body weight of 72.0 ± 3.4 kg were included in the study. Before treatment, all ten gilts underwent surgical implantation of an indwelling venous catheter to allow repeated blood samplings for pharmacokinetic assessment. On Day 3 after surgery, each gilt received an intramuscular injection of 100 μg buserelin acetate (25 mL of 4 μg/mL Receptal, MSD Animal Health, USA). Blood samples (5 mL each) were collected 14 times from each gilt via the jugular catheter at the following time points: 0, 2, 5, 10, 15, 20, 30, and 45 min, as well as 1, 1.5, 2, 3, 4, and 6 h post-injection. Blood samples were collected into heparinized tubes, centrifuged to separate the plasma, and stored at -20°C until analysis. Plasma buserelin concentrations were then determined using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The LC-MS/MS system operated in positive ion mode using electrospray ionization with multiple reaction monitoring. Buserelin was quantified based on precursor/product ion pairs identified in the chromatogram. The calibration curve for buserelin acetate in pig plasma showed high linearity (R² ≥ 0.99), with a lower limit of quantification of 0.30 μg/L. The findings showed that the average maximum plasma concentration (C_max) of buserelin acetate was 2.21 ± 0.72 μg/L, occurring at 0.30 ± 0.10 h (T_max) after administration. The elimination half-life (T_1/2) was 0.51 ± 0.03 h. The area under the concentration-time curve from 0 to the last measurement point (AUC_0-t) was 7.30 ± 0.87 μg·h/L. The clearance rate (CL) was 0.20 ± 0.03 L/h/kg, and the apparent volume of distribution (Vd) was 0.13 ± 0.05 L/kg. These results suggest that buserelin acetate from Receptal is rapidly metabolized and eliminated in gilts, emphasizing the need for precise timing of administration to maintain effective drug concentrations.

P-glycoprotein (P-gp) greatly impacts substrate drug disposition, so much so that regulatory agencies recommend ascertaining the P-gp status of active pharmaceutical ingredients (APIs) intended for human use. Arguably, the P-gp status of drugs intended for canine patients is equally, if not more, important. Our research objectives were to assess whether human P-gp substrate data can predict canine P-gp substrate status and to explore the three previously reported binding sites within the P-gp binding pocket, the H-, R-, and P-sites. Competitive efflux assays employing cell lines expressing canine or human P-gp were used to compare the degree of overlap or independence of the three binding sites in canine versus human P-gp using site-specific fluorescent P-gp substrates rhodamine 123, calcein AM and Hoechst 33342. Because calcein AM can also be transported by multidrug resistance protein 1 (MRP1), experiments were performed to assess its potential influence on calcein AM efflux studies. Results indicate that: (i) MRP1 is either a non-factor or negligible factor for cells expressing canine or human P-gp respectively; (ii) determining an API's P-gp binding site may provide clinically relevant information; and (iii) use of human P-gp substrate data as a proxy for canine P-gp substrate data will often prove inaccurate.

Porcine respiratory diseases is a major cause of economic losses in livestock, and ceftiofur is one of the core therapeutic agents for its treatment, but the clinical efficacy can be inconsistent. Therefore, it is necessary to utilize a population pharmacokinetic model to reveal the distribution and metabolic patterns of ceftiofur in pig populations, while also combining Monte Carlo simulation techniques to predict the probability of treatment success under different dosing regimens. To investigate the probability of attaining the pharmacokinetic/pharmacodynamic targets of ceftiofur in pigs infected with different respiratory bacteria, a population pharmacokinetic model for the intramuscular administration of ceftiofur in pigs was developed, and Monte Carlo simulation was performed to analyze the target attainment rate of ceftiofur at different doses. The results showed that the target attainment rate of ceftiofur was 100% for Pasteurella multocida at the dose of 0.5 mg/kg b.w. intramuscularly, 99.9% for Actinobacillus pleuropneumoniae at 1 mg/kg b.w. intramuscularly, 93.4% for Streptococcus suis at 0.5 mg/kg b.w. intramuscularly, and 95.4% for Haemophilus parasuis at 10 mg/kg b.w. intramuscularly. The results indicate that it is crucial to optimize the dosage based on specific infected bacteria to improve the success rate of treatment and extend the clinical application period of ceftiofur.