Journal of veterinary pharmacology and therapeutics最新文献

Diazepam (DZP), a benzodiazepine medication, is extensively utilized in both human and veterinary medicine and has been frequently detected in fish populations. The use of DZP-laced bait is identified as a predominant contributor to drug residue contamination in fish. Nonetheless, our understanding of the residue profile of DZP in fish and its potential implications for human health remains constrained. This study investigated the residue behavior and dietary intake risks of DZP and its primary metabolites in crucian carp (Carassius auratus) following oral administration. A rapid and sensitive UHPLC–MS/MS method was developed and validated for the reliable quantification of DZP and its identified metabolites. The findings revealed rapid absorption and extensive distribution of DZP in crucian carp, with peak concentrations in plasma and tissues occurring at 1 h. The distribution pattern of DZP, based on calculated AUC, was kidney > liver > plasma > gill > muscle plus skin. The distribution of DZP in plasma and tested tissues followed the decreasing order of kidney > liver > plasma > gill > muscle plus skin according to the calculated AUC. DZP elimination was notably slow, particularly in muscle plus skin, with an elimination half-life of 619.31 h, necessitating at least 70 days for concentrations to fall below the limit of quantitation, suggesting a high likelihood of residue formation in fish from oral DZP administration. DZP was metabolized into nordiazepam and temazepam in crucian carp; nordiazepam is the main metabolite of DZP, which is gradually higher than the parent drug in the elimination phase. The dietary risk assessment suggested that a possible health risk (HQ ≥ 0.1) was found within 1 day via ingestion of crucian carp after an oral dose of DZP, suggesting that frequent consumption of high-residue crucian carp may cause harm to human health.

Oxycodone, a full mu opioid receptor agonist prescribed for moderate-to-severe pain in people, could provide outpatient analgesia for dogs with post-operative or cancer pain. To determine the pharmacokinetic profile and physiological side effects of a single oral (PO) dose, five healthy, 2-year-old, castrated male hounds were administered a standard amount of food, with or without immediate-release oxycodone (1 mg/kg), in random order, separated by 1 month. At intervals between 0.25 and 8 h later, blood was sampled to measure plasma oxycodone concentration using ultra high-pressure liquid chromatography with mass spectrometry detection, and vital signs were evaluated. Pharmacokinetic variables were estimated using noncompartmental analysis. Maximum plasma concentration (C_max) was 58.6 (39.3, 61.6) ng/mL, time to maximal plasma concentration (t_max) was 1.5 (0.5, 2.0) h, elimination half-life (t_1/2el) was 2.6 (2.0, 6.7) h, area under the curve from time 0 to last measurement (AUC_0-t) was 236.1 (204.6, 256.0) ng-h/mL, and mean residence time (MRT) was 3.9 (3.4, 9.8) h. Computer simulations using the calculated pharmacokinetic data predicted that 1 mg/kg PO every 6 h would achieve peak (C_max) and trough (minimum plasma concentration, C_min) of 69.4 (60.8, 74.6) and 17.0 (15.5, 46.7), respectively, at steady state. Assuming minimum effective analgesic concentration is similar in humans and dogs (~25 mg/mL), therapeutic concentrations were achieved, but administration more frequently than every 6 h would be necessary. Oxycodone produced a significantly lower rectal temperature 1 and 4 h after administration.

The clinical breakpoint for a drug–pathogen combination reflects the drug susceptibility of the pathogen wild-type population, the location of the infection, the integrity of the host immune response, and the drug–pathogen pharmacokinetic (PK)/pharmacodynamic (PD) relationship. That PK/PD relationship, along with the population variability in drug exposure, is used to determine the probability of target attainment (PTA) of the PK/PD index at a specified minimum inhibitory concentration (MIC) for a selected target value. The PTA is used to identify the pharmacodynamic cutoff value (CO_PD), which is one of the three components used to establish the clinical breakpoint. A challenge encountered when defining the CO_PD is that the available PK information typically reflects total (free plus protein-bound) plasma concentrations. However, it is the unbound drug concentrations that exert the therapeutic effects and how the population fraction unbound (fu) incorporated into the CO_PD assessments can markedly influence the CO_PD. Factors examined included the estimated population fu mean (risk of bias) and the incorporation of estimated fu population variability into the Monte Carlo simulations when converting total to unbound plasma concentrations (risk of inflating variability). In this in silico study, the drug fu, systemic clearance, and the variability of both were altered so that the relative impact of each could be explored. We demonstrate that incorporating fu variability into the estimation of fAUCback can bias the CO_PD assessment and that the magnitude of bias reflects the relative variability in systemic clearance and fu.

Parasitic infestations are one of the most economically important disease conditions in the Indian major carps including mrigal, Cirrhinus mrigala. This study reported the biosafety and tissue withdrawal of in-feed administered antiparasitic drug, emamectin benzoate (EMB). To evaluate the biosafety of the drug, behaviour, growth and tissue changes in Cirrhinus mrigala was recorded the following in-feed administration of EMB up to 10 times (T1–50 μg kg⁻¹ fish day⁻¹ (1×), T2–125 μg kg⁻¹ fish day⁻¹ (2.5×), T3–250 μg kg⁻¹ fish day⁻¹ (5×), T4–375 μg kg⁻¹ fish day⁻¹ (7.5×) and T5–500 μg kg⁻¹ fish day⁻¹ (10×)) for the period of three times the recommended duration (7 days). The withdrawal period was calculated by feeding EMB at 50 μg kg⁻¹ fish day⁻¹ for consecutive 10 days followed by EMB-free feed. The results revealed that the drug is safe to mrigal up to ten times the recommended dose, while the fish fed with the highest dose (500 μg kg⁻¹ fish day⁻¹) showed transient histological alterations. The feeding behaviour is affected with poor acceptability beyond 5× dosages. The drug residue at the concentration below the MRL (1.0 μg g⁻¹) in the muscle tissue on the day of cessation of medicated feed administration indicates no requirement of the withdrawal period. The study suggests that EMB can be safely used at 50 μg kg⁻¹ fish day⁻¹ for 7 consecutive days, and no withdrawal period is required without affecting the feeding behaviour and tissue histological alterations.

The objective of this study was to implement population pharmacokinetic (PPK) of enrofloxacin (EF) in grass carp (Ctenopharyngodon idella) after a single oral administration and a single intravenous administration based on a nonlinear mixed effect model. The plasma samples collected by the sparse sampling method were detected by high-performance liquid chromatography with a fluorescent detector. The initial pharmacokinetic (PK) parameters were evaluated by reference search and the calculation of a naïve pooled method. After oral administration, the concentration–time profile was best described by a one-compartment open model. The absorption rate constant (K_a), apparent distribution volume (V), and systemic clearance (CL) were estimated to be 3.11/h, 4.36 L/kg, and 0.079 L/h/kg, respectively. After intravenous administration, the concentration–time curve was best simulated by a two-compartment open model. The apparent distribution volume of the central compartment (V₁), apparent distribution volume of the peripheral compartment (V₂), CL, and clearance from the central compartment to the peripheral compartment (CL₂) were estimated to be 0.42, 2.05 L/kg, 0.067, and 2.94 L/h/kg, respectively. Finally, the bioavailability was calculated to be 84.81%. The parameter of AUC/minimum inhibitory concentration value was estimated to be more than 506.32 for Aeromonas hydrophila, Aeromonas sobria, and Flavobacterium columnare indicating that EF at 20 mg/kg has high effectiveness for these pathogens. This study supported a concise method for conducting PK study in aquatic animals that facilitated the development of PK methodology in aquaculture.