Pharmacokinetics of ganciclovir and valganciclovir in the adult horse

Equine herpes myeloencephalopathy, resulting from equine herpes virus type 1 (EHV‐1) infection, is associated with substantial morbidity and mortality in the horse. As compared to other antiviral drugs, such as acyclovir, ganciclovir has enhanced potency against EHV‐1. This study investigated the pharmacokinetics of ganciclovir and its oral prodrug, valganciclovir, in six adult horses in a randomized cross‐over design. Ganciclovir sodium was administered intravenously as a slow bolus at a dose of 2.5 mg/kg, and valganciclovir was administered orally at a dose of 1800 mg per horse. Intravenously administered ganciclovir disposition was best described by a three‐compartment model with a prolonged terminal half‐life of 72 ± 9 h. Following the oral administration of valganciclovir, the mean observed maximum serum ganciclovir concentration was 0.58 ± 0.37 μg/mL, and bioavailability of ganciclovir from oral valganciclovir was 41 ± 20%. Superposition predicted that oral dosing of 1800‐mg valganciclovir two times daily would fail to produce and maintain effective plasma concentrations of ganciclovir. However, superposition suggested that i.v. administration of ganciclovir at 2.5 mg/kg every 8 h for 24 h followed by maintenance dosing of 2.5 mg/kg every 12 h would maintain effective ganciclovir serum concentrations in most horses throughout the dosing interval.     

Hematological adverse effects and pharmacokinetics of ribavirin in pigs following intramuscular administration

Ribavirin (RBV) is a synthetic guanosine analog that is used as a drug against various viral diseases in humans. The in vitro antiviral effects of ribavirin against porcine viruses were demonstrated in several studies. The purposes of this study were to evaluate the adverse effects and pharmacokinetics of ribavirin following its intramuscular (IM) injection in pigs. Ribavirin was formulated as a double‐oil emulsion (RBV‐DOE) and gel (RBV‐Gel), which were injected into the pigs as single‐dose IM injections. After injection of RBV, all of the pigs were monitored. The collected serum and whole blood samples were analyzed by liquid chromatography–tandem mass spectrometry and complete blood count analysis, respectively. All of the ribavirin‐treated pigs showed significant decreases in body weight compared to the control groups. Severe clinical signs including dyspnea, anorexia, weakness, and depression were present in ribavirin‐treated pigs until 5 days postinjection (dpi). The ribavirin‐treated groups showed significant decrease in the number of red blood cells and hemoglobin concentration until 8 dpi. The mean half‐life of the RBV‐DOE and RBV‐Gel was 27.949 ± 2.783 h and 37.374 ± 3.502 h, respectively. The mean peak serum concentration (C_max) and area under the serum concentration–time curve from time zero to infinity (AUC_inf) of RBV‐DOE were 8340.000 ± 2562.577 ng/mL and 16 0095.430 ± 61 253.400 h·ng/mL, respectively. The C_max and AUC_inf of RBV‐Gel were 15 300.000 ± 3764.306 ng/mL and 207526.260 ± 63656.390 h·ng/mL, respectively. The results of this study provided the index of side effect and pharmacokinetics of ribavirin in pigs, which should be considered before clinical application.     

Pharmacokinetics of metronidazole in foals: influence of age within the neonatal period

Neonatal foals have unique pharmacokinetics, which may lead to accumulation of certain drugs when adult horse dosage regimens are used. Given its lipophilic nature and requirement for hepatic metabolism, metronidazole may be one of these drugs. The purpose of this study was to determine the pharmacokinetic profiles of metronidazole in twelve healthy foals at 1–2.5 days of age when administered as a single intravenous (IV) and intragastric (IG) dose of 15 mg/kg. Foals in the intravenous group were studied a second time at 10–12 days of age to evaluate the influence of age on pharmacokinetics within the neonatal period. Blood samples were collected at serial time points after metronidazole administration. Metronidazole concentration in plasma was measured using LC‐MS. Pharmacokinetic parameters were determined using noncompartmental analysis and compared between age groups. At 1–2.5 days of age, the mean peak plasma concentration after IV infusion was 18.79 ± 1.46 μg/mL, elimination half‐life was 11.8 ± 1.77 h, clearance was 0.84 ± 0.13 mL/min/kg and the volume of distribution (steady‐state) was 0.87 ± 0.07 L/kg. At 10–12 days of age, the mean peak plasma concentration after IV infusion was 18.17 ± 1.42 μg/mL, elimination half‐life was 9.07 ± 2.84 h, clearance was 1.14 ± 0.21 mL/min/kg and the volume of distribution (steady‐state) was 0.88 ± 0.06 L/kg. Oral approximated bioavailability was 100%. Cmax and T_max after oral dosing were 14.85 ± 0.54 μg/mL and 1.75 (1–4) h, respectively. The elimination half‐life was longer and clearance was reduced in neonatal foals at 1–2.5 days as compared to 10–12 days of age (P = 0.006, P = 0.001, respectively). This study warrants consideration for altered dosing recommendations in foals, especially a longer interval (12 h).     

Study of pharmacokinetics of an in situ forming gel system for controlled delivery of florfenicol in pigs

To reduce florfenicol (FFC) administration frequency in veterinary use, the drug was currently developed into in situ forming gel. Twelve pigs were randomly divided into two groups (six pigs per group). A single i.m. dose of 40 mg/kg body weight (b.w.) was given to pigs, group one was given FFC in situ forming gel, and group two was given FFC conventional injection. High‐performance liquid chromatography (HPLC) was used to determine FFC plasma concentrations. There were significant differences (P < 0.01) between FFC in situ forming gel and conventional injection, in pharmacokinetic parameters MRT (mean retention time) (57.79 ± 2.88) h versus (15.94 ± 1.29) h, AUC (area under the concentration–time curve) (421.54 ± 8.97) μg·h/mL versus (168.16 ± 4.59) μg·h/mL, t_max (time of occurrence of c_max) (9.00 ± 2.68) h versus (4.33 ± 0.82) h, c_max (maximum plasma concentration) (6.87 ± 0.66) μg/mL versus (12.01 ± 0.66) μg/mL, t_1/2λz (terminal elimination half‐life) (38.04 ± 2.20) h versus (9.15 ± 2.71) h. The results demonstrated that the in situ forming gel system could shorten dosing interval of FFC and thus achieved less frequent administration during long‐term treatment.     

Pharmacokinetic parameters for single‐ and multi‐dose regimens for subcutaneous administration of a high‐dose ceftiofur crystalline‐free acid to neonatal foals

The objective of this study was to determine the pharmacokinetics of single‐ and multi‐dose ceftiofur crystalline‐free acid (CCFA) administered subcutaneously at a dose of 13.2 mg/kg to 12 neonatal foals 1–3 days of age. Six foals received a single subcutaneous dose, while 6 additional foals received 4 doses of CCFA at 48‐h intervals. Blood samples were collected at pre‐determined times following drug administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured using high‐performance liquid chromatography. Following single‐dose administration of CCFA, the mean ± standard deviation maximum observed plasma concentration was 3.1 ± 0.6 μg/mL and observed time to maximal plasma concentration was 14.0 ± 4.9 h. Following multi‐dose administration of CCFA, the mean ±standard deviation times above CFAE concentrations of ≥0.5 μg/mL and ≥2.0 μg/mL were 192.95 ± 15.86 h and 78.80 ± 15.31 h, respectively. The mean ± standard deviation area under the concentration vs time curve (AUC_0→∝) was 246.2 ± 30.7 h × μg/mL and 172.7 ± 27.14 h × μg/mL following single‐ and multi‐dose CCFA administrations, respectively. Subcutaneous administration of CCFA at 13.2 mg/kg in neonatal foals was clinically well‐ tolerated and resulted in plasma concentrations sufficient for the treatment of most bacterial pathogens associated with neonatal foal septicemia. Multi‐dose administration of four doses at dosing interval of 48 h between treatments maintains appropriate therapeutic concentrations in neonatal foals.     

The influence of Actinobacillus pleuropneumoniae infection on tulathromycin pharmacokinetics and lung tissue disposition in pigs

A tulathromycin concentration and pharmacokinetic parameters in plasma and lung tissue from healthy pigs and Actinobacillus pleuropneumoniae (App)‐infected pigs were compared. Tulathromycin was administered intramuscularly (i.m.) to all pigs at a single dose of 2.5 mg/kg. Blood and lung tissue samples were collected during 33 days postdrug application. Tulathromycin concentration in plasma and lung was determined by high‐performance liquid chromatography with tandem mass spectrometry (LC‐MS/MS) method. The mean maximum plasma concentration (C_max) in healthy pigs was 586 ± 71 ng/mL, reached by 0.5 h, while the mean value for C_max of tulathromycin in infected pigs was 386 ± 97 ng/mL after 0.5 h. The mean maximum tulathromycin concentration in lung of healthy group was calculated as 3412 ± 748 ng/g, detected at 12 h, while in pigs with App, the highest concentration in lung was 3337 ± 937 ng/g, determined at 48 h postdosing. The higher plasma and lung concentrations in pigs with no pulmonary inflammation were observed at the first time points sampling after tulathromycin administration, but slower elimination with elimination half‐life t_1/2el = 126 h in plasma and t_1/2el = 165 h in lung, as well as longer drug persistent in infected pigs, was found.     

Pharmacokinetic/pharmacodynamic relationship of cefquinome against Pasteurella multocida in a tissue‐cage model in yellow cattle

The cephalosporin antimicrobial drug cefquinome was administered to yellow cattle intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1 mg/kg of body weight in a two‐period crossover study. The pharmacokinetic (PK) properties of cefquinome in serum, inflamed tissue‐cage fluid (exudate), and noninflamed tissue‐cage fluid (transudate) were studied using a tissue‐cage model. The in vitro and ex vivo activities of cefquinome in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. A concentration‐independent antimicrobial activity of cefquinome was confirmed for levels lower than 4 × MIC. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the time that drug levels remain above the MIC (T > MIC) in serum was 14.10 h after intravenous and 14.46 h after intramuscular dosing, indicating a likely high level of effectiveness in clinical infections caused by P. multocida of MIC 0.04 μg/mL or less. These data may be used as a rational basis for setting dosing schedules, which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.     

Pharmacokinetics of danofloxacin and N‐desmethyldanofloxacin in adult horses and their concentration in synovial fluid

The objectives of this study were to investigate the pharmacokinetics of danofloxacin and its metabolite N‐desmethyldanofloxacin and to determine their concentrations in synovial fluid after administration by the intravenous, intramuscular or intragastric routes. Six adult mares received danofloxacin mesylate administered intravenously (i.v.) or intramuscularly (i.m.) at a dose of 5 mg/kg, or intragastrically (IG) at a dose of 7.5 mg/kg using a randomized Latin square design. Concentrations of danofloxacin and N‐desmethyldanofloxacin were measured by UPLC‐MS/MS. After i.v. administration, danofloxacin had an apparent volume of distribution (mean ± SD) of 3.57 ± 0.26 L/kg, a systemic clearance of 357.6 ± 61.0 mL/h/kg, and an elimination half‐life of 8.00 ± 0.48 h. Maximum plasma concentration (C_max) of N‐desmethyldanofloxacin (0.151 ± 0.038 μg/mL) was achieved within 5 min of i.v. administration. Peak danofloxacin concentrations were significantly higher after i.m. (1.37 ± 0.13 μg/mL) than after IG administration (0.99 ± 0.1 μg/mL). Bioavailability was significantly higher after i.m. (100.0 ± 12.5%) than after IG (35.8 ± 8.5%) administration. Concentrations of danofloxacin in synovial fluid samples collected 1.5 h after administration were significantly higher after i.v. (1.02 ± 0.50 μg/mL) and i.m. (0.70 ± 0.35 μg/mL) than after IG (0.20 ± 0.12 μg/mL) administration. Monte Carlo simulations indicated that danofloxacin would be predicted to be effective against bacteria with a minimum inhibitory concentration (MIC) ≤0.25 μg/mL for i.v. and i.m. administration and 0.12 μg/mL for oral administration to maintain an area under the curve:MIC ratio ≥50.     

Intravenous infusion of electrolyte solution changes pharmacokinetics of drugs: pharmacokinetics of ampicillin

The pharmacokinetics of ampicillin in dogs was determined after intravenous (i.v.) bolus and constant rate infusion. Ampicillin was administered to six beagle dogs as an i.v. bolus at 20 mg/kg and as a constant rate i.v. infusion (CRI) at 20 mg/kg during 8 h (0.042 mL/min/kg) in Ringer's lactate (Hartmann's) solution. The concentrations were determined by an LC/MS/MS method. After i.v. bolus, ampicillin total body clearance, apparent volume of distribution at steady‐state, mean residence time (MRT), and half‐life were 4.53 ± 0.70 mL/min/kg, 0.275 ± 0.044 L/kg, 61 ± 13 min, and 111 (85–169) min, respectively. The corresponding parameters calculated after CRI were 13.5 ± 1.06 mL/min/kg, 0.993 ± 0.415 L/kg, 73 ± 27 min, and 49 (31–69) min. Ampicillin concentration decreased by 30% in the Ringer's lactate infusion solution mostly during the first hour after preparation of the solution. Constant rate infusion of Ringer's lactate solution during 8 h caused significant changes in ampicillin pharmacokinetics. The results suggested that special attention should be given to drug pharmacokinetics when co‐administered intravenously with electrolyte solutions.     

Pharmacokinetic study of meropenem in healthy beagle dogs receiving intermittent hemodialysis

Meropenem, a second carbapenem antimicrobial agent with a broad spectrum of activity, is used to treat sepsis and resistant‐bacterial infections in veterinary medicine. The objective of this study was to identify the pharmacokinetics of meropenem in dogs receiving intermittent hemodialysis (IHD) and to determine the proper dosing in renal failure patients receiving IHD. Five healthy beagle dogs were given a single i.v. dose of 24 mg/kg of meropenem and received IHD. The blood flow rate, dialysate flow, and ultrafiltration rate were maintained at 40 mL/min, 300 mL/min, and 40 mL/h, respectively. Blood samples were collected for 24 h from the jugular vein and from the extracorporeal arterial and venous line. Urine samples and dialysate were also collected. The concentrations of meropenem were assayed using HPLC/MS/MS determination. The peak plasma concentration was 116 ± 37 μg/mL at 15 min. The systemic clearance was 347 ± 117 mL/h/kg, and the steady‐state volume of distribution was 223 ± 67 mL/kg. Dialysis clearance was 71.1 ± 34.3 mL/h/kg, and the extraction ratio by hemodialysis was 0.455 ± 0.150. The half‐life (T_1/2) in dogs with IHD decreased compared with those without IHD, and the reduction in T_1/2 was greater in renal failure patients than in normal patients. Sixty‐nine percent and 21% of the administered drug were recovered by urine and dialysate in the unchanged form, respectively. In conclusion, additional dosing of 24 mg/kg of meropenem after dialysis could be necessary according to the residual renal function of the patient based on the simulated data.     

Comparative pharmacokinetics of minocycline in foals and adult horses

The objective of this study was to compare the pharmacokinetics of minocycline in foals vs. adult horses. Minocycline was administered to six healthy 6‐ to 9‐week‐old foals and six adult horses at a dose of 4 mg/kg intragastrically (IG) and 2 mg/kg intravenously (i.v.) in a cross‐over design. Five additional oral doses were administered at 12‐h intervals in foals. A microbiologic assay was used to measure minocycline concentration in plasma, urine, synovial fluid, and cerebrospinal fluid (CSF). Liquid chromatography–tandem mass spectrometry was used to measure minocycline concentrations in pulmonary epithelial lining fluid (PELF) and bronchoalveolar (BAL) cells. After i.v. administration to foals, minocycline had a mean (±SD) elimination half‐life of 8.5 ± 2.1 h, a systemic clearance of 113.3 ± 26.1 mL/h/kg, and an apparent volume of distribution of 1.24 ± 0.19 L/kg. Pharmacokinetic variables determined after i.v. administration to adult horses were not significantly different from those determined in foals. Bioavailability was significantly higher in foals (57.8 ± 19.3%) than in adult horses (32.0 ± 18.0%). Minocycline concentrations in PELF were higher than in other body fluids. Oral minocycline dosed at 4 mg/kg every 12 h might be adequate for the treatment of susceptible bacterial infections in foals.     

Pharmacokinetics of meloxicam in mature swine after intravenous and oral administration

The purpose of this study was to compare the pharmacokinetics of meloxicam in mature swine after intravenous (i.v.) and oral (p.o.) administration. Six mature sows (mean bodyweight ± standard deviation = 217.3 ± 65.68 kg) were administered an i.v. or p.o. dose of meloxicam at a target dose of 0.5 mg/kg in a cross‐over design. Plasma samples collected up to 48 h postadministration were analyzed by high‐pressure liquid chromatography and mass spectrometry (HPLC‐MS) followed by noncompartmental pharmacokinetic analysis. Mean peak plasma concentration (C_MAX) after p.o. administration was 1070 ng/mL (645–1749 ng/mL). T_MAX was recorded at 2.40 h (0.50–12.00 h) after p.o. administration. Half‐life (T½ λ_z) for i.v. and p.o. administration was 6.15 h (4.39–7.79 h) and 6.83 h (5.18–9.63 h), respectively. The bioavailability (F) for p.o. administration was 87% (39–351%). The results of this study suggest that meloxicam is well absorbed after oral administration.     

Pharmacokinetic evaluation of ceftiofur in serum, tissue chamber fluid and bronchial secretions from healthy beef-bred calves.

Ceftiofur is a new broad spectrum cephalosporin marketed for the treatment of acute bovine respiratory disease. In this investigation ceftiofur was administered by intramuscular injection, at 24 h intervals, to healthy beef-bred calves for four days at dosages of 2.2 and 4.4 mg/kg of body weight, with 4 wk intervals between dosing regimens. Serum, tissue chamber fluid (TCF), and bronchial secretion (BS) concentrations of ceftiofur were measured by microbiological assay after the first and fourth dose of each dosing regimen. Peak serum concentrations (Cmax) of 8.8 micrograms/mL and 17.3 micrograms/mL were obtained approximately 2 h (Tmax), the time of mean peak concentration) after single injections of 2.2 mg/kg and 4.4 mg/kg, respectively. The Cmax was increased approximately twofold following multiple doses of 2.2 mg/kg (Cmax = 13.1 micrograms/mL) and 4.4 mg/kg (Cmax = 24.1 micrograms/mL). Ceftiofur accumulated slowly into TCF and peak concentrations were found to be approximately 14% of those observed in serum after the first dose and approximately 24% after multiple dosing. Concentrations of ceftiofur in BS were obtained rapidly with peak concentrations reaching 45% of the serum Cmax after the first dose. After multiple dosing the Cmax for BS was approximately 25% of the serum Cmax. This study found that both the 2.2 mg/kg and 4.4 mg/kg dosing regimens resulted in continuous serum, TCF and BS concentrations of ceftiofur that exceeded the minimal concentration required to inhibit the bacteria most frequently isolated from calves with acute bovine respiratory disease.     

Pharmacokinetics of a modified,compounded theophylline product in dogs

Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP‐compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6 mg/kg theophylline equivalent) and oral MCT (10 mg/kg). Systemic bioavailability of the MCT was 96.2 ± 32.9%. MCT times to maximum concentration, mean absorption time and terminal half‐life were 8.85 ± 3.63, 6.95 ± 3.42, and 8.67 ± 1.62 hr, respectively. Based on simulations of 10 mg/kg and 12‐hr dosing, steady‐state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7 ± 35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended‐release theophylline products. An oral dose of 10 mg/kg q 12 hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter‐individual variation.     

Pharmacokinetics and physiologic effects of alprazolam after a single oral dose in healthy mares

The objective of this study was to evaluate the pharmacokinetic properties and physiologic effects of a single oral dose of alprazolam in horses. Seven adult female horses received an oral administration of alprazolam at a dosage of 0.04 mg/kg body weight. Blood samples were collected at various time points and assayed for alprazolam and its metabolite, α‐hydroxyalprazolam, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of alprazolam was analyzed by a one‐compartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single‐dose administration of alprazolam were as follows: C_max 14.76 ± 3.72 ng/mL and area under the curve (AUC_0–∞) 358.77 ± 76.26 ng·h/mL. Median (range) T_max was 3 h (1–12 h). Alpha‐hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (C_max 1.36 ± 0.28 ng/mL). Repeat physical examinations and assessment of the degree of sedation and ataxia were performed every 12 h to evaluate for adverse effects. Oral alprazolam tablets were absorbed in adult horses and no clinically relevant adverse events were observed. Further evaluation of repeated dosing and safety of administration of alprazolam to horses is warranted.     

Dietary levels of protein and free amino acids affect pancreatic proteases activities,amino acids transporters expression and serum amino acid concentrations in starter pigs

The dietary contents of crude protein and free amino acids (AA) may affect the protein digestion and AA absorption in pigs. Trypsin and chymotrypsin activities, AA serum concentrations and expression of AA transporters in the small intestine of pigs fed a low protein, AA‐supplemented (19.2%, LPAA) or a high protein (28.1%, HP), wheat‐soybean meal diet were measured in two 14‐d trials. The LPAA diet contained free L‐Lys, L‐Thr, DL‐Met, L‐Leu, L‐Ile, L‐Val, L‐His, L‐Trp and L‐Phe. All pigs were fed the same amount of feed (890 and 800 g/d for trial 1 and 2 respectively). In trial 1, samples of mucosa (duodenum, jejunum and ileum) and digesta (duodenum and jejunum) were collected from 14 pigs (17.2 ± 0.4 kg); in trial 2, blood samples were collected from 12 pigs (12.7 ± 0.3 kg). The trypsin and chymotrypsin activities in both intestinal segments were higher in pigs fed the HP diet (p < 0.01). Trypsin activity was higher in jejunum than in duodenum regardless the dietary treatment (p < 0.05). Pigs fed the LPAA diet expressed more b^0,+AT in duodenum, B⁰AT1 in ileum (p < 0.05), and tended to express more y⁺LAT1 in duodenum (p = 0.10). In pigs fed the LPAA diet, the expression of b^0,+AT was higher in duodenum than in jejunum and ileum (p < 0.01), but no difference was observed in pigs fed the HP diet. Ileum had the lowest b^0,+AT expression regardless the diet. The serum concentrations of Lys, Thr and Met were higher in LPAA pigs while serum Arg was higher in HP pigs (p < 0.05). Serum concentrations of AA appear to reflect the AA absorption. In conclusion, these data indicate that the dietary protein contents affect the extent of protein digestion and that supplemental free AA may influence the intestinal site of AA release and absorption, which may impact their availability for growth of young pigs.     

Pharmacokinetics and selected pharmacodynamics of romifidine following low‐dose intravenous administration in combination with exercise to quarter horses

Romifidine is an alpha‐2 adrenergic agonist used for sedation and analgesia in horses. As it is a prohibited substance, its purported use at low doses in performance horses necessitates further study. The primary goal of the study reported here was to describe the serum concentrations and pharmacokinetics of romifidine following low‐dose administration immediately prior to exercise, utilizing a highly sensitive liquid chromatography–tandem mass spectrometry assay that is currently employed in many drug testing laboratories. An additional objective was to describe changes in heart rate and rhythm following intravenous administration of romifidine followed by exercise. Eight adult Quarter Horses received a single intravenous dose of 5 mg (0.01 mg/kg) romifidine followed by 1 h of exercise. Blood samples were collected and drug concentrations measured at time 0 and at various times up to 72 h. Mean ± SD systemic clearance, steady‐state volume of distribution and terminal elimination half‐life were 34.1 ± 6.06 mL/min/kg and 4.89 ± 1.31 L/kg and 3.09 ± 1.18 h, respectively. Romifidine serum concentrations fell below the LOQ (0.01 ng/mL) and the LOD (0.005 ng/mL) by 24 h postadministration. Heart rate and rhythm appeared unaffected when a low dose of romifidine was administered immediately prior to exercise.     

Disposition of a long‐acting oxytetracycline formulation in Thai swamp buffaloes (Bubalus bubalis)

The present study aimed to characterize the pharmacokinetic profile of oxytetracycline long‐acting formulation (OTC‐LA) in Thai swamp buffaloes, Bubalus bubalis, following single intramuscular administration at two dosages of 20 and 30 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 504 h. The plasma concentrations of OTC were measured by high‐performance liquid chromatography (HPLC). The concentrations of OTC in the plasma were determined up to 264 h and 432 h after i.m. administration at doses of 20 and 30 mg/kg b.w., respectively. The C_max values of OTC were 12.11 ± 1.87 μg/mL and 12.27 ± 1.92 μg/mL at doses of 20 and 30 mg/kg, respectively. The AUC_last values increased in a dose‐dependent fashion. The half‐life values were 52.00 ± 14.26 h and 66.80 ± 10.91 h at doses of 20 and 30 mg/kg b.w, respectively. Based on the pharmacokinetic data and PK–PD index (T > MIC), i.m. administration of OTC at a dose of 30 mg/kg b.w once per week might be appropriate for the treatment of susceptible bacterial infection in Thai swamp buffaloes.     

Pharmacokinetics of buprenorphine following intravenous and buccal administration in cats,and effects on thermal threshold

This study reports the pharmacokinetics of buprenorphine, following i.v. and buccal administration, and the relationship between buprenorphine concentration and its effect on thermal threshold. Buprenorphine (20 μg/kg) was administered intravenously or buccally to six cats. Thermal threshold was determined, and arterial blood sampled prior to, and at various times up to 24 h following drug administration. Plasma buprenorphine concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to the time–concentration data. Pharmacokinetic/pharmacodynamic models were fitted to the concentration‐thermal threshold data. Thermal threshold was significantly higher than baseline 44 min after buccal administration, and 7, 24, and 104 min after i.v. administration. A two‐ and three‐compartment model best fitted the data following buccal and i.v. administration, respectively. Following i.v. administration, mean ± SD volume of distribution at steady‐state (L/kg), clearance (mL·min/kg), and terminal half‐life (h) were 11.6 ± 8.5, 23.8 ± 3.5, and 9.8 ± 3.5. Following buccal administration, absorption half‐life was 23.7 ± 9.1 min, and terminal half‐life was 8.9 ± 4.9 h. An effect‐compartment model with a simple effect maximum model best predicted the time‐course of the effect of buprenorphine on thermal threshold. Median (range) k_e0 and EC50 were 0.003 (0.002–0.018)/min and 0.599 (0.073–1.628) ng/mL (i.v.), and 0.017 (0.002–0.023)/min and 0.429 (0.144–0.556) ng/mL (buccal).