Journal of veterinary pharmacology and therapeutics最新文献

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.

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.

Cluster seizures and status epilepticus in dogs are emergencies requiring rapid intervention. Intranasal (IN) benzodiazepines are effective for early seizure cessation, but the pharmacokinetics of longer-acting antiseizure medications administered IN have not been investigated in dogs. This study aimed to describe the single-dose pharmacokinetics of a compounded IN levetiracetam product (IN-LEV) in healthy dogs. We hypothesized that the administration of IN-LEV to healthy dogs will demonstrate similar pharmacokinetic parameters to IV administration. In a randomized crossover design, nine healthy dogs received a single 30 mg/kg IV dose (100 mg/mL) or a single 30 mg/kg IN dose (460 mg/mL) of levetiracetam. Serum levetiracetam concentrations were serially measured over 24 h. Pharmacokinetic analysis was performed using non-compartmental methods and comparisons between routes of administration were made using the Wilcoxon signed-rank test. C_max, T_max, and t_1/2 for IN-LEV were 14.6 ± 5.4 μg/mL, 2.3 ± 1.5 h, and 3.6 ± 0.4 h, respectively. IN-LEV achieved minimum target concentrations (5 μg/mL) within 0.34 ± 0.22 h and maintained these levels for 6.57 ± 3.17 h. Bioavailability for IN-LEV was 70% ± 27.4%. This study demonstrates that IN levetiracetam rapidly achieves the lowest reference interval concentration, but the high end of the interval was not achieved in any dog with a single 30 mg/kg dose. IN-LEV may be a viable alternative for emergent seizure management when IV access is unavailable, but multiple doses may be required to achieve seizure cessation in some patients.

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.

Whitespotted bamboo sharks (Chiloscyllium plagiosum) are a common species of elasmobranchs housed in zoos and aquaria. Medical concerns like conspecific trauma and bacterial infections commonly lead to the empirical use of antibiotic medications like ceftazidime, despite limited pharmacokinetic studies in elasmobranchs. In this study, 36 whitespotted bamboo sharks were divided into six groups using a population pharmacokinetic design. They were administered a single intramuscular injection of ceftazidime at 20 mg/kg. Blood samples were collected for plasma drug concentration at time points T = 0 and 30 min, and 1, 2, 4, 6, 12, 24, 48, 72, and 96 h post-injection. Samples were analyzed by the Clinical Pharmacology Laboratory in the College of Veterinary Medicine of North Carolina State University using high-pressure liquid chromatography (HPLC) analysis. For at least 96 h, all sharks in the study maintained plasma concentrations of ceftazidime above the MIC of 4 μg/mL, which is considered susceptible when testing isolates from other animals. The long elimination half-time of 84.15 h suggests that recommended dosing intervals may be extended beyond the commonly used 3 days to at least every 96 h.

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.

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.

The fluoroquinolone antimicrobial agents, enrofloxacin and marbofloxacin, were approved in the United States for cats in 1990 and 2001, respectively. In 2023, revised breakpoints for testing isolates from dogs were published. These canine breakpoints are discordant with the current feline breakpoints. This study was aimed at suggesting new feline breakpoints using a pharmacokinetic-pharmacodynamic (PK-PD) approach and new pharmacokinetic data. The PK-PD derived cutoff values (CO_PD) were compared to microbiologic data available for testing the susceptibility of targeted pathogens since the original approval. Compared to the current Clinical and Laboratory Standards Institute (CLSI) breakpoints for enrofloxacin and marbofloxacin in cats, these revised breakpoints are lower by two dilutions for the Enterobacterales, Pseudomonas aeruginosa, Staphylococcus spp., and Pasteurella multocida. Isolates that may have previously tested susceptible (S) may test resistant (R) using these suggested breakpoints. We also are suggesting a susceptible dose-dependent (SDD) category for testing marbofloxacin against these isolates from cats that allows for a higher dose. These suggested breakpoints may be considered by laboratories, standard-setting organizations, and industry sponsors of these antimicrobials for testing common bacteria isolated from cats.