Journal of veterinary pharmacology and therapeutics最新文献

The pharmacokinetics and pharmacodynamics of betamethasone following intra-articular administration to horses have been described; however, studies characterizing intramuscular administration are lacking. Twenty-four horses received an intramuscular dose of 12 mg betamethasone sodium phosphate/betamethasone acetate. Blood and urine were collected at post administration for up to 408 h. Concentrations of betamethasone were determined using LC-MS/MS and pharmacokinetic parameters determined using a Population PK three-compartment model. The duration of pharmacodynamic effects was assessed by measuring changes in cortisol and inflammatory biomarkers utilizing an ex vivo model. The C_max, T_max, and terminal half-life of betamethasone were 6.43 ± 1.70 ng/mL, 0.75 (0.5-2.0 h; median and range), and 30.5 ± 20.4 h, respectively. Covariates were not found to have significant effects on the variability of pharmacokinetic parameters. Based on Monte Carlo simulations, for 1000 horses, a detection time of 23 days is recommended for concentrations to fall below the screening limit of 10 pg/mL in 99% of the population. Urine concentrations were above the limit of quantitation in 2/24 horses at 408 h. Suppression of cortisol lasted for 360 h. Effects on inflammatory biomarker production lasted for a prolonged period. An extended withdrawal time for intramuscular administration prior to competition is warranted.

Antimicrobial drugs are commonly used for the treatment of bacterial diseases in cobia (Rachycentron canadum), but information regarding the rationale of their therapeutic use, such as pharmacokinetics (PK), optimal dosages, and withdrawal time (WDT) in this species is very rare. The present study evaluated the PK characteristics of florfenicol (FF) in cobia at 25°C after a single oral administration of 10 mg/kg via medicated feed. FF in the serum was determined by an HPLC method and the PK parameters were analyzed by a one-compartmental model. In tissue depletion and drug WDT study, cobia were fed with FF medicated feed at 10 mg/kg once daily for 5 days. The WDT was determined by linear regression analysis using the sum of FF and its metabolite florfenicol amine as the marker residue. The results revealed that FF has desirable PK characteristics in cobia, including a high peak serum concentration (C_max, 9.08 μg/mL), a large area under the serum concentration-time curve (AUC, 182.68 h·μg/mL), and a moderately long elimination half-life (t_1/2K, 10.22 h). The optimal dosage for a minimum inhibitory concentration (MIC) of 2 μg/mL at 25°C was 6.23 mg/kg/day. The WDT was calculated to be 5 days based on muscle/skin and 6 days based on serum depletion. Since serum sampling can reduce animal use, it warrants further investigation despite not being an official target tissue for WDT. Our findings indicated that FF is a good choice for treating bacterial diseases in cobia due to its favorable PK profile and short WDT.

The aim of the study was to determine the exposure to subcutaneously administered butorphanol in horses pre-treated with intravenous (IV) detomidine, with or without vatinoxan, a peripherally selective alpha₂-adrenoceptor antagonist. Five healthy, adult horses received three IV treatments 7 days apart, in a randomized, cross-over design: detomidine 20 μg/kg (DET-B), detomidine 20 μg/kg with vatinoxan 200 μg/kg (DETVAT-B) and saline (S-B), all followed by 0.1 mg/kg of butorphanol administered subcutaneously 30 min later. Venous samples were collected between 10 and 270 min after butorphanol administration. Butorphanol concentrations in plasma were analyzed with liquid chromatography coupled with triple quadruple mass spectrometry. Data were analyzed with non-compartmental methods. The observed areas under plasma butorphanol concentration-time curves were 8104 ± 2590, 7042 ± 2628 and 5996 ± 1670 ng·min/mL for DET-B, DETVAT-B and S-B, respectively. There were no significant differences between treatments. Pre-treatment with detomidine, with or without vatinoxan, did not significantly affect the exposure to subcutaneously administered butorphanol in this study.

Ursodeoxycholic acid (UDCA), a secondary bile acid (BA) with therapeutic applications, is standard therapy for cholestatic hepatopathies in humans. In recent years, its use has been increasingly explored in equine medicine for similar indications. Pharmacokinetic data for UDCA in horses are currently lacking. This study aimed to describe the pharmacokinetic parameters following a single intragastric administration of 15 mg/kg in nine healthy, fasted horses and to characterize the changes in their BA profiles. Plasma concentrations of UDCA were measured at specific time points using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic analysis revealed a sharp increase in plasma concentrations within the first 1-3 h, with peak concentrations (Tmax) occurring at 2.44 ± 1.3 h. Plasma concentrations decreased significantly in most horses at 24 h, with negligible concentrations detected at 48-72 h. Mean half-life was calculated at 7.99 ± 2.25 h, and the dose interval estimate mean was 24.29 h. BA profile analysis demonstrated an increase in total BA concentrations post-administration, with a notable rise in the percentage of UDCA relative to other BAs. Based on these findings, we conclude that the intragastric dose of 15 mg/kg every 24 h is appropriate for horses. Clinicians should be aware that, post-administration, total BA concentrations are likely to increase within hours, with UDCA becoming the predominant BA.

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.

The increasing frequency of bacterial diseases in aquaculture has necessitated the use of several antibiotics, including enrofloxacin (ENF), a broad-spectrum fluoroquinolone. The pharmacokinetic (PK) and pharmacodynamic (PD) data on ENF under tropical aquaculture conditions remain scarce. This study investigated the PK profile, tissue accumulation, and depletion pattern of total active fluoroquinolone (ENF + CIP) in Nile tilapia Oreochromis niloticus following a single oral dose of 10 mg/kg biomass. The ENF demonstrated rapid absorption, with peak plasma concentration (C_max) of 1.33 ± 0.21 μg/mL at 0.59 h (T_max), and extensive tissue distribution, particularly in bile (C_max: 16.26 ± 0.50 μg/mL) and intestine (C_max: 7.08 ± 0.28 μg/g). Elimination half-lives (t_1/2β) varied among tissues, with prolonged persistence in skin (t_1/2β: 693.18 h) and gills (t_1/2β: 237.47 h), indicating slow depletion. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ENF indicated its high effectiveness against Aeromonas hydrophila (0.20 μg/mL), while Streptococcus agalactiae exhibited comparatively lower sensitivity (MIC: 1.56 μg/mL; MBC: 6.25 μg/mL). The PK/PD integration revealed that ENF achieved optimal therapeutic levels against A. hydrophila, but suboptimal levels for S. agalactiae under a single-dose regimen. These findings underscore the need for tailored dosing strategies and highlight the importance of pharmacokinetic and microbiological data for responsible antibiotic use in aquaculture.

The objectives of this study were to evaluate ATIP pharmacokinetics (PK) in healthy Beagle dogs after IM and IN dosing (Phase I), and to compare the rate of reversal of IM versus IN routes for xylazine (XYL) sedation (Phase II). This study was comprised of two sequential, randomized, crossover experiments. The initial PK study dosed ATIP by IN and IM routes without XYL sedation. In the second phase, dogs were sedated with XYL prior to ATIP reversal. Their sedation scores were monitored during this period, and blood sampling began 20 min post reversal. ATIP was quantified in plasma using a validated HPLC-MS/MS method. Plasma concentrations of ATIP rapidly increased and declined after both routes, but C_max and AUC were higher after IM dosing (p < 0.001). Relative IN bioavailability was 33%-50% of the IM dose. Xylazine reversal of sedation was more rapid after IM versus IN ATIP (p < 0.01), but both routes produced complete reversal within 40 min. In conclusion, IN ATIP was slower than IM for reversing XYL sedation but is a viable route if parenteral administration is not an option. Adjusting the labeled IM ATIP dose may be warranted for IN use to account for lower bioavailability.

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.