Pharmacokinetics of amikacin in the horse following intravenous and intramuscular administration

The pharmacokinetics of amikacin sulfate (AK) were studied in the horse after intravenous (i.v.) and intramuscular (i.m.) administration. Serum (Cs), synovial (Csf) and peritoneal (Cpf) fluid concentrations of the drug were measured. Doses of 4.4, 6.6 and 11.0 mg/kg were given. The concentrations at 15 min following i.v. injection were 30.3 +/- 0.3, 61.2 +/- 6.9 and 122.8 +/- 7.4 micrograms/ml, respectively, for the 4.4, 6.6 and 11.0 mg/kg doses. Mean peak Cs values after the intramuscular injections occurred at 1.0 h post-injection and were 13.3 +/- 1.6, 23.0 +/- 0.6 and 29.8 +/- 3.2 micrograms/ml, respectively. The t 1/2 of amikacin was 1.44, 1.57 and 1.14 h for the 4.4, 6.6 and 11.0 mg/kg doses, respectively. In this study, minimum inhibitory concentrations (MIC) of amikacin sulfate were determined for six pathogens. Based on the MIC and the pharmacokinetic parameters, it would appear that the usual therapeutic dose of amikacin would be between 4.4 and 6.6 mg/kg twice daily and, for the more serious life-threatening infections, dosing three times a day.     

Pharmacokinetics and pharmacodynamics of butorphanol following intravenous administration to the horse

Knych, H. K., Casbeer, H. C., McKemie, D. S., Arthur, R. M. Pharmacokinetics and pharmacodynamics of butorphanol following intravenous administration to the horse. J. vet. Pharmacol. Therap.  36 , 21–30. Butorphanol is a narcotic analgesic commonly used in horses. Currently, any detectable concentration of butorphanol in biological samples collected from performance horses is considered a violation. The primary goal of the study reported here was to update the pharmacokinetics of butorphanol following intravenous administration, utilizing a highly sensitive liquid chromatography‐mass spectrometry (LC‐MS) assay that is currently employed in many drug‐testing laboratories. An additional objective was to characterize behavioral and cardiac effects following administration of butorphanol. Ten exercised adult horses received a single intravenous dose of 0.1 mg/kg butorphanol. Blood and urine samples were collected at time 0 and at various times for up to 120 h and analyzed using LC‐MS. Mean ± SD systemic clearance, steady‐state volume of distribution, and terminal elimination half‐life were 11.5 ± 2.5 mL/min/kg, 1.4 ± 0.3 L/kg, and 5.9 ± 1.5 h, respectively. Butorphanol plasma concentrations were below the limit of detection (LOD) (0.01 ng/mL) by 48 h post administration. Urine butorphanol concentrations were below the LOD (0.05 ng/mL) of the assay in seven of 10 horses by 120 h post drug administration. Following administration, horses appeared excited as noted by an increase in heart rate and locomotion. Gastrointestinal sounds were markedly decreased for up to 24 h.     

The pharmacokinetics of orbifloxacin in the horse following oral and intravenous administration

The purpose of this study was to determine the pharmacokinetics and physicochemical characteristics of orbifloxacin in the horse. Six healthy adult horses were administered oral and intravenous orbifloxacin at a dose of 2.5 mg/kg. Plasma samples were collected and analyzed by high-pressure liquid chromatography with ultraviolet detection. Plasma protein binding and lipophilicity were determined in vitro . Following i.v. administration, orbifloxacin had a terminal half-life ( t _1/2) of 5.08 h and a volume of distribution (V_d(ss)) of 1.58 L/kg. Following oral administration, the average maximum plasma concentration ( C _max) was 1.25  μ g/mL with a t _1/2 of 3.42 h. Systemic bioavailability was 68.35%. Plasma protein binding was 20.64%. The octanol:water partition coefficient (pH 7.4) was 0.2 ± 0.11. No adverse reactions were noted during this study. Dosage regimens were determined from the pharmacokinetic–pharmacodynamic parameters established for fluoroquinolone antibiotics. For susceptible bacteria, an oral dose of approximately 5 mg/kg once daily will produce plasma concentrations within the suggested range. This dose is suggested for further studies on the clinical efficacy of orbifloxacin for treatment of susceptible bacterial infections in the horse.     

Pharmacokinetics of fenbendazole following intravenous and oral administration to pigs

OBJECTIVE: To determine pharmacokinetics and metabolic patterns of fenbendazole after IV and oral administration to pigs. ANIMALS: 4 mixed-breed female pigs weighing 32 to 45 kg. PROCEDURE: Fenbendazole was administered IV at a dose of 1 mg/kg. One week later, it was administered orally at a dose of 5 mg/kg. Blood samples were collected for up to 72 hours after administration, and plasma concentrations of fenbendazole, oxfendazole, and fenbendazole sulfone were determined by use of high-pressure liquid chromatography. Plasma pharmacokinetics were determined by use of noncompartmental methods. RESULTS: Body clearance of fenbendazole after IV administration was 1.36 L/h/kg, volume of distribution at steady state was 3.35 L/kg, and mean residence time was 2.63 hours. After oral administration, peak plasma concentration of fenbendazole was 0.07 microg/ml, time to peak plasma concentration was 3.75 hours, and mean residence time was 15.15 hours. Bioavailability of fenbendazole was 27.1%. Oxfendazole was the major plasma metabolite, accounting for two-thirds of the total area under the plasma concentration versus time curve after IV and oral administration. Fenbendazole accounted for 8.4% of the total AUC after IV administration and 4.5% after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that fenbendazole was rapidly eliminated from plasma of pigs. The drug was rapidly absorbed after oral administration, but systemic bioavailability was low.     

Pharmacokinetics of phenobarbital in the cat following intravenous and oral administration.

Phenobarbital was administered to eight healthy cats as a single intravenous dose of 10 mg/kg. Serum phenobarbital concentrations were determined using an immunoassay technique. The intravenous data were fitted to one-, two- and three-compartment models. After statistical comparison of the three models, a two-compartment model was selected. Following intravenous administration, the drug was rapidly distributed (distribution half-life = 0.046 +/- 0.007 h) with a large apparent volume of distribution (931 +/- 44.8 mL/kg). Subsequent elimination of phenobarbital from the body was slow (elimination half-life = 58.8 +/- 4.21 h). Three weeks later, a single oral dose of phenobarbital (10 mg/kg) was administered to the same group of cats. A one-compartment model with an input component was used to describe the results. After oral administration, the initial rapid absorption phase (absorption half-life = 0.382 +/- 0.099 h) was followed by a plateau in the serum concentration (13.5 +/- 0.148 micrograms/mL) for approximately 10 h. The half-life of the terminal elimination phase (76.1 +/- 6.96 h) was not significantly different from the half-life determined for the intravenous route. Bioavailability of the oral drug was high (F = 1.20 +/- 0.120). Based on the pharmacokinetic parameters determined in this study, phenobarbital appears to be a suitable drug for use as an anticonvulsant in the cat.     

Pharmacokinetics of buprenorphine following intravenous and oral transmucosal administration in dogs

Pharmacokinetic analysis of buprenorphine administered to six healthy dogs via the oral transmucosal (OTM) route at doses of 20 and 120 microg/kg was conducted using liquid chromatography-electrospray ionization-tandem mass spectroscopy (LC-ESI-MS/MS). Bioavailability was 38% plus or minus 12% for the 20 microg/kg dose and 47%+/-16% for the 120 microg/kg dose. Maximum plasma concentrations were similar for buprenorphine doses of 20 microg/kg IV and 120 microg/kg OTM. Sedation and salivation were common side effects, but no bradycardia, apnea, or cardiorespiratory depressive effects were seen. When the two OTM dosing rates were normalized to dose, LC-ESI-MS/MS analysis of buprenorphine and its metabolites detected no significant difference (P>.05), indicating dose proportionality. The results of this study suggest that OTM buprenorphine may be an alternative for pain management in dogs.     

Pharmacokinetics of gatifloxacin in broiler chickens following intravenous and oral administration

1. The pharmacokinetics of gatifloxacin were investigated following intravenous and oral administration of a single dose at a rate of 10?mg/kg body weight in broiler chicks.

2. Drug concentration in plasma was determined using High Performance Liquid Chromatography with ultraviolet detection on samples collected at frequent intervals after drug administration.

3. Following intravenous administration, the drug was rapidly distributed (t_1/2α: 0·33?±?0·008?h) and eliminated (t_1/2β: 3·62?±?0·03?h; Cl_B: 0·48?±?0·002?l/h/kg) from the body.

4. After oral administration, the drug was rapidly absorbed (C _max: 1·74?±?0·024?µg/mL; T _max: 2?h) and slowly eliminated (t_1/2β: 3·81?±?0·07?h) from the body. The apparent volume of distribution (V_d(area)), total body clearance (Cl_B) and mean residence time (MRT) were 3·61?±?0·04?l/kg, 0·66?±?0·01?l/h/kg and 7·16?±?0·08?h, respectively. The oral bioavailability of gatifloxacin was 72·96?±?1·10 %.

5. Oral administration of gatifloxacin at 10?mg/kg is likely to be highly efficacious against susceptible bacteria in broiler chickens.     

Pharmacokinetics of clomipramine in dogs following single-dose intravenous and oral administration

OBJECTIVE: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs after IV or oral administration of a single dose. ANIMALS: 6 male and 6 female Beagles. PROCEDURES: Clomipramine was administered IV (2 mg/kg), PO (4 mg/kg) after food was withheld for 15 hours, and PO (4 mg/kg) within 25 minutes after dogs were fed. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method. RESULTS: Time to peak plasma concentrations of clomipramine and desmethylclomipramine following oral administration was 1.2 hours. For clomipramine, after IV administration, elimination half-life was 5 hours, mean residence time was 3 hours, and plasma clearance was 1.4 L/h/kg. Values for mean residence time and terminal half-life following oral administration were similar to values obtained following IV administration, and systemic bioavailability was approximately 20% for clomipramine and 140% for desmethylclomipramine, indicating fast absorption of clomipramine from the gastrointestinal tract and extensive first-pass metabolism. Administration of clomipramine with food did not alter the area under the concentration versus time curve for desmethylclomipramine but resulted in a 25% increase for clomipramine. Clomipramine and desmethylclomipramine were extensively bound (> 96%) to serum proteins. There were no significant differences in area under the concentration versus time curve between male and female dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that there should not be any clinically important differences in efficacy regardless of whether clomipramine is administered with or without food.     

Pharmacokinetics of thymoquinone in layer chickens following oral and intravenous administration

Thymoquinone (TQ) is the major constituent of Nigella sativa and known to possess a variety of pharmacological effects. This study was designed to evaluate the pharmacokinetic profile of TQ following oral (PO) and intravenous (IV) administration in layer chickens. The layer chickens were equally divided into two groups (six chickens in each group, total 12 chickens), and TQ was administered via PO and IV routes. For PO route, the dose was 20 mg/kg b.w. and for IV route, 5 mg/kg b.w. was administered, respectively. A sensitive and accurate High‐Performance Liquid Chromatography (HPLC) technique was validated for the quantification of TQ from plasma. The limit of detection (LOD) and limit of quantification (LOQ) were 0.02 µg/ml and 0.05 µg/ml, respectively with >80% recovery. Maximum plasma concentration (C_max) following PO and IV administration was 8.805 and 4.497 µg/ml, respectively, while time to reach at maximum concentration (T_max) was 1 and 0.1 hr, respectively. The elimination half‐lives were recorded as 1.02 and 0.978 hr, whereas the mean residence times were 1.79 and 1.036 hr following both PO and IV administration, respectively. The 85% PO bioavailability was indicative that TQ could be used for various therapeutic purposes in layer chickens.     

Pharmacokinetics of azathioprine following single-dose intravenous and oral administration and effects of azathioprine following chronic oral administration in horses

OBJECTIVE: To determine pharmacokinetics of azathioprine (AZA) and clinical, hematologic, and serologic effects of i.v. and oral administration of AZA in horses. ANIMALS: 6 horses. PROCEDURE: In study phase 1, a single dose of AZA was administered i.v. (1.5 mg/kg) or orally (3.0 mg/kg) to 6 horses, with at least 1 week between treatments. Blood samples were collected for AZA and 6-mercaptopurine (6-MP) analysis 1 hour before and at predetermined time points up to 4 hours after AZA administration. In study phase 2, AZA was administered orally (3 mg/kg) every 24 hours for 30 days and then every 48 hours for 30 days. Throughout study phase 2, blood samples were collected for CBC determination and serum biochemical analysis. RESULTS: Plasma concentrations of AZA and its metabolite, 6-MP decreased rapidly from plasma following i.v. administration of AZA, consistent with the short mean elimination half-life of 1.8 minutes. Oral bioavailability of AZA was low, ranging from 1% to 7%. No horses had abnormalities on CBC determination or serum biochemical analysis, other than 1 horse that was lymphopenic on day 5 and 26 of daily treatment. This horse developed facial alopecia from which 1 colony of a Trichophyton sp was cultured; alopecia resolved within 1 month after the study ended. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, no adverse effects were observed with long-term oral administration of AZA to horses, although 1 horse did have possible evidence of immunosuppression with chronic treatment. Further investigation of the clinical efficacy of AZA in the treatment of autoimmune diseases in horses is warranted.     

Pharmacokinetics of voriconazole following intravenous and oral administration and body fluid concentrations of voriconazole following repeated oral administration in horses

OBJECTIVE: To determine the pharmacokinetics of voriconazole following IV and PO administration and assess the distribution of voriconazole into body fluids following repeated PO administration in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURES: All horses received voriconazole (10 mg/kg) IV and PO (2-week interval between treatments). Plasma voriconazole concentrations were determined prior to and at intervals following administration. Subsequently, voriconazole was administered PO (3 mg/kg) twice daily for 10 days to all horses; plasma, synovial fluid, CSF, urine, and preocular tear film concentrations of voriconazole were then assessed. RESULTS: Mean +/- SD volume of distribution at steady state was 1,604.9 +/- 406.4 mL/kg. Systemic bioavailability of voriconazole following PO administration was 95 +/- 19%; the highest plasma concentration of 6.1 +/- 1.4 microg/mL was attained at 0.6 to 2.3 hours. Mean peak plasma concentration was 2.57 microg/mL, and mean trough plasma concentration was 1.32 microg/mL. Mean plasma, CSF, synovial fluid, urine, and preocular tear film concentrations of voriconazole after long-term PO administration were 5.163 +/- 1.594 microg/mL, 2.508 +/- 1.616 microg/mL, 3.073 +/- 2.093 microg/mL, 4.422 +/- 0.8095 microg/mL, and 3.376 +/- 1.297 microg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that voriconazole distributed quickly and widely in the body; following a single IV dose, initial plasma concentrations were high with a steady and early decrease in plasma concentration. Absorption of voriconazole after PO administration was excellent, compared with absorption after IV administration. Voriconazole appears to be another option for the treatment of fungal infections in horses.     

Pharmacokinetics and renal clearance of oxytetracycline in piglets following intravenous and oral administration

The pharmacokinetics of oxytetracycline (OTC) in three weaned piglets was studied following three routes of administration: intravenously, orally as drench, both at a dose of 20 mg/kg, and orally as medicated (400 ppm OTC) pelleted feed administered during 3 consecutive days. Analysis of the intravenous data according to the three compartment pharmacokinetic model revealed that OTC was well distributed in the body (Vf: 1.62 l/kg), had an overall body clearance of 0.25 litre/kg/h, and the elimination half-lives were in the range between 11.6 and 17.2 hrs. The mean OTC binding to plasma proteins was 75.5 +/- 4%. Following the drench route of administration the maximum plasma OTC concentration was achieved between 1 and 5 h post application and ranged between 1.18 and 1.41 micrograms/ml. The mean maximum plasma OTC concentration during medicated feed administration was 0.20 +/- 0.06 microgram/ml, which was achieved approximately 30 hours after the onset of the administration. A steady state OTC plasma level (approximately 0.2 microgram/ml) was maintained till the end of the trial. Within 48 hours after cessation of medicated feed administration the plasma OTC levels were beneath 0.06 microgram/ml. The mean OTC bioavailabilities of the oral routes were low: after the drench route of administration 9.0 +/- 0.67%, and after medicated pelleted feed administration 3.69 +/- 0.8%. The mean OTC renal clearances of each piglet ranged between 10.1 and 13.9 ml/min/kg (based on free OTC plasma fractions). The renal OTC clearance values were urine flow dependent in all piglets and significantly correlated with the renal creatinine clearance (P less than 0.005), being 3-5 times higher than the latter. It is concluded that in piglets OTC is excreted mainly by glomerular filtration and partly by tubular secretion. The potential clinical efficacy of 400 ppm OTC as medicated feed with respect to treatment, e.g. atrophic rhinitis, is discussed.     

Pharmacokinetics and renal clearance of oxytetracycline in piglets following intravenous and oral administration

Summary

The pharmacokinetics of oxytetracycline (OTC) in three weaned piglets was studied following three routes of administration: intravenously, orally as drench, both at a dose of 20 mg/kg, and orally as medicated (400 ppm OTC) pelleted feed administered during 3 consecutive days. Analysis of the intravenous data according to the three compartment pharmacokinetic model revealed that OTC was well distributed in the body (Vie 1.621/kg), had an overall body clearance of 0.25 litre/kg/h, and the elimination half‐lives were in the range between 11.6 and 17.2 hrs.

The mean OTC binding to plasma proteins was 75.5 ± 4%. Following the drench route of administration the maximum plasma OTC concentration was achieved between 1 and 5 h post application and ranged between 1.18 and 1.41 μg/ml. The mean maximum plasma OTC concentration during medicated feed administration was 0.20 ± 0.06 μg/ml, which was achieved approximately 30 hours after the onset of the administration. A steady state OTC plasma level (approximately 0.2 μg/ml) was maintained till the end of the trial. Within 48 hours after cessation of medicated feed administration the plasma OTC levels were beneath 0.06 μg/ml. The mean OTC bioavailabilities of the oral routes were low: after the drench route of administration 9.0 ± 0.67%, and after medicated pelleted feed administration 3.69 ± 0.8%.

The mean OTC renal clearances of each piglet ranged between 10.1 and 13.9 ml/min/kg (based on free OTC plasma fractions). The renal OTC clearance values were urine flow dependent in all piglets and significantly correlated with the renal creatinine clearance (P< 0.005), being 3–5 times higher than the latter. It is concluded that in piglets OTC is excreted mainly by glomerular filtration and partly by tubular secretion. The potential clinical efficacy of 400 ppm OTC as medicated feed with respect to treatment, e.g. atrophic rhinitis, is discussed.     

Pharmacokinetics of tetracycline in the domestic rabbit following intravenous or oral administration.

Tetracycline hydrochloride was administered to domestic rabbits using a single bolus by the intravenous and oral routes. Pharmacokinetic parameters were determined for intravenous (10 mg/kg) and oral (150 mg/kg) administration. The effect of fasting for 12 h on the drug elimination kinetics after oral administration was evaluated. Tetracycline was added to the drinking water at 800 mg/L or 1600 mg/L. Drug and water intake and serum levels were monitored. Mean serum pharmacokinetic parameters following intravenous administration were; 0 intercept beta curve B (microgram/mL) = 7.5, rate of elimination from body -b (min-1) = 0.0058, half life elimination from body -t 1/2 b (min) = 120.0, wt(kg) = 3.2 determined using combined male and female data. Mean serum pharmacokinetic parameters after oral administration (single bolus) were -B (microgram/mL) = 1.54 (full stomach) and 2.71 (empty stomach), b(min-1) = 0.0037 (full stomach) and 0.0035 (empty stomach), t 1/2 b (min) = 190.3 (full stomach) and 216.2 (empty stomach). Administration of tetracycline in the drinking water produced very low to nondetectable levels of drug in the serum, even at high dosage, and the 1600 mg/L drug concentration was accompanied by a significant drop in water intake. Thus, it is evident that concentrations of tetracycline of up to 1600 mg/L drinking water will not produce levels of antibiotic consistently detectable in the serum.     

Pharmacokinetics of ibafloxacin following intravenous and oral administration to healthy Beagle dogs

The pharmacokinetics of ibafloxacin, a new veterinary fluoroquinolone antimicrobial agent, was studied following intravenous (i.v.) and oral administration to healthy dogs. The mean absolute bioavailability of ibafloxacin after oral doses of 7.5, 15 and 30 mg/kg ranged from 69 to 81%, indicating that ibafloxacin was well absorbed by dogs. Ibafloxacin was also absorbed rapidly [time of maximum concentration (t(max)) 1.5 h], reaching a mean maximum concentration (C(max)) of 6 microg/mL at 15 mg/kg, well distributed in the body [large volume of distribution at steady state (V(ss)) and V(area) of 1.1 L/kg and 4 L/kg, respectively], and exhibited an elimination half-life of 5.2 h and a low total body clearance (8.7 mL/min/kg). Both C(max) and area under the concentration-time curve (AUC) showed dose proportionality over the dose range tested (7.5-30 mg/kg). The pharmacokinetics of ibafloxacin was similar following single and repeated dosage regimens, implying no significant accumulation in plasma. Food promoted the absorption of ibafloxacin by increasing C(max) and AUC, but did not change t(max). High amounts of the metabolites, mainly 8-hydroxy- and, 7-hydroxy-ibafloxacin were excreted in urine and faeces, either unchanged or as glucuronide conjugates. Following oral administration of 15 mg ibafloxacin/kg, the total recovery of ibafloxacin, its metabolites and conjugates in urine and faeces was 61.9-99.9% of the dose within 48 h.     

Pharmacokinetics of intravenous and oral methimazole following single-and multiple-dose administration in normal cats

The pharmacokinetics of methimazole (MMI) administered intravenously and orally were determined in six adult domestic shorthaired cats. There was no significant difference between mean serum MMI concentrations after oral and i.v. administration by 30 min post-MMI administration, indicating relatively rapid and complete absorption of the drug. The bioavailability of MMI ranged from 27% to 100% (mean = 81.1 +/- 11.4%). The mean serum elimination half-life was 6.6 +/- 2.0 h, with a wide range of values (1.9 h to 15.1 h). After repeat i.v. administration of MMI following 2 weeks of oral administration of the drug, no significant difference was found between mean serum concentrations after single-dose and multiple-dose administration. No significant change in serum elimination half-life or total body clearance was found after multiple-dose administration of MMI. Two cats with the longest half-lives (9.9 h and 15.1 h), however, did exhibit markedly shorter t1/2 values (3.5 h and 3.3 h, respectively) after multiple-dose administration. Values for central and steady state volumes of distribution also decreased after multiple-dose administration, possibly indicating saturation of thyroid uptake of MMI with chronic administration. These results indicate that MMI has good oral bioavailability and has a longer mean serum elimination half-life than propylthiouracil, the other anti-thyroid drug that has been evaluated in cats. Although no significant change in mean values occurred after multiple-dose administration of MMI, drug-induced acceleration of metabolism may occur in some cats after long-term MMI administration.