Pharmacokinetic disposition of a long-acting oxytetracycline formulation after single-dose intravenous and intramuscular administrations in the American alligator (Alligator mississippiensis).

The pharmacokinetics of a long-acting oxytetracycline preparation administered i.v. and i.m. to American alligators (Alligator mississippiensis) at 10 mg/kg was determined. Plasma levels of oxytetracycline were measured using high-performance liquid chromatography, and the resulting concentration versus time curve was analyzed using compartmental modeling and noncompartmental modeling techniques for i.v. and i.m. samples, respectively. A two-compartment model best represented the i.v. data. Intravenous administration of oxytetracycline resulted in an extrapolated mean plasma concentration at time zero of 60.63 +/- 28.26 microg/ml, with average plasma drug levels of 2.82 +/- 0.71 microg/ml at the end of the 192-hr sampling period. Plasma volume of distribution for i.v. oxytetracycline was 0.20 +/- 0.09 L/kg, with a harmonic mean elimination half-life of 15.15 hr and mean total body clearance rate of 0.007 +/- 0.002 L/hr/kg. Intramuscular administration of oxytetracycline achieved a mean peak plasma concentration of 6.85 +/- 1.96 microg/ml at 1 hr after administration, with average plasma drug levels of 4.96 +/- 1.97 microg/ml at the end of the 192-hr sampling period. The harmonic mean terminal elimination half-life for i.m. oxytetracycline was 131.23 hr. Based on the results of this study, long-acting preparations of oxytetracycline administered parenterally to American alligators at 10 mg/kg q 5 days is expected to maintain plasma concentrations above the minimum inhibitory concentration of 4.0 microg/ml for susceptible organisms.     

Pharmacokinetics after intravenous and oral administration of enrofloxacin in sheep

OBJECTIVE: To compare pharmacokinetics of enrofloxacin administered IV and in various oral preparations to ewes. ANIMALS: 5 mature Katahdin ewes weighing 42 to 50 kg. PROCEDURE: Ewes received 4 single-dose treatments of enrofloxacin in a nonrandomized crossover design followed by a multiple-dose oral regimen. Single-dose treatments consisted of an IV bolus of enrofloxacin (5 mg/kg), an oral drench (10 mg/kg) made from crushed enrofloxacin tablets, oral administration in feed (10 mg/kg; mixture of crushed enrofloxacin tablets and grain), and another type of oral administration in feed (10 mg/kg; mixture of enrofloxacin solution and grain). The multiple-dose regimen consisted of feeding a mixture of enrofloxacin solution and grain (10 mg/kg, q 24 h, for 7 days). Plasma concentrations of enrofloxacin and ciprofloxacin were measured by use of high-performance liquid chromatography. RESULTS: Harmonic mean half-life for oral administration was 14.80, 10.80, and 13.07 hours, respectively, for the oral drench, crushed tablets in grain, and enrofloxacin solution in grain. Oral bioavailability for the oral drench, crushed tablets in grain, and enrofloxacin in grain was 4789, 98.07, and 94.60%, respectively, and median maximum concentration (Cmax) was 1.61, 2.69, and 2.26 microg/ml, respectively. Median Cmax of the multiple-dose regimen was 2.99 microg/ml. CONCLUSIONS AND CLINICAL RELEVANCE: Enrofloxacin administered orally to sheep has a prolonged half-life and high oral bioavailability. Oral administration at 10 mg/kg, q 24 h, was sufficient to achieve a plasma concentration of 8 to 10 times the minimum inhibitory concentration (MIC) of any microorganism with an MIC < or = 0.29 microg/ml.     

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and oral administration of enrofloxacin in dogs

Rung, K., Riond, J.-L. & Wanner, M. Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin after intravenous and oral administration of enrofloxacin in dogs. J. vet
Four dogs were given 5 mg/kg body weight enrofloxacin intravenously (i.v.) and orally (p.o.) in a cross-over study. Plasma concentrations of the active ingredient enrofloxacin and its main metabolite ciprofloxacin were determined by a reversed phase liquid chromatographic method. Pharmacokinetic parameters of both substances were calculated by use of statistical moments and were compared to those of enrofloxacin described in the veterinary literature. Mean enrofloxacin t _½λZ was 2.4 h, mean Cl_s was 27.1 ml/min-kg, and mean V_ss was 7.0 1/kg. After i.v. and p.o. administration, concentrations of ciprofloxacin exceeding minimal inhibitory concentrations of several microorganisms were reached (C_max= 0.2 ng/ml, max = 2.2 h after intravenous administration; C_max= 0.2 (ig/ml, t _max= 3.6 h after oral administration). A considerable part of the antimicrobial activity is due to ciprofloxacin, the main metabolite of enrofloxacin.     

Plasma concentrations of enrofloxacin after single-dose oral administration in loggerhead sea turtles (Caretta caretta).

Plasma concentrations and pharmacokinetics of enrofloxacin were determined in 12 loggerhead sea turtles (Caretta caretta) after oral administration. Six turtles in group 1 and group 2 received enrofloxacin at 10 mg/kg and 20 mg/kg of body weight, respectively. Blood was collected from the cervical sinus before administration and at timed intervals up to 168 hr following administration. Plasma concentrations of enrofloxacin were determined using a microbiologic assay. The mean peak plasma concentration (Cmax) was 4.07 microg/ml and 21.30 microg/ml for groups 1 and 2, respectively. Plasma levels were detectable at 168 hr postadministration, with mean values of 0.380 microg/ml for group I and 2.769 microg/ml for group 2. The mean elimination half-life for enrofloxacin was 37.80 hr for group I and 54.42 hr for group 2. These findings indicated that enrofloxacin is absorbed following oral administration in loggerhead sea turtles, and blood levels are maintained up to 168 hr following administration.     

Effects of bacterial lipopolysachharide on peripheral leukocytes in the American alligator (Alligator mississippiensis)

Alligators were injected intraperitoneally with four different doses (10, 1.0, 0.1, and 0.01 mg/kg body weight) of a mixture of bacterial lipopolysaccharides (LPS) derived from three different types of bacteria (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae). Injection of the alligators with the LPS mixture resulted in a dose- and time-dependent increase in total peripheral leukocytes Lymphocytes increased at days 3 and 4 post-injection, and decreased back to baseline levels at day 7 for all doses. Alligators that were not treated, and those injected with pyrogen-free saline, did not exhibit statistically significant changes in total leukocytes during the course of the study. Injection of alligators with 0.5 mg LPS/kg body weight derived from one of three bacterial species revealed that the leukocyte increases observed were not statistically different for all three types of LPS. The animals displayed the same increases in total counts and the levels of all circulating leukocyte types were not different between animals treated with a combination of LPS from all three bacterial species.     

Broad spectrum antimicrobial activity of leukocyte extracts from the American alligator (Alligator mississippiensis)

Leukocytes were isolated from whole blood of wild alligators by differential sedimentation. The leukocytes were disrupted in 5% AcOH and the crude extracts processed by ultrafiltration. The extracts were subjected to solvent exchange (0.1% AcOH) and the fraction that contained macromolecules between 1 and 10 kDa were subjected to further analyses. The acid extracts of the alligator leukocytes exhibited substantial antimycotic activities against six of eight species of Candida yeast tested. In addition, the alligator leukocyte extracts were effective as antimicrobial agents against 10 of 12 bacterial species, and displayed moderate activity against two enveloped viruses (human immunodeficiency virus-1 and herpes simplex virus-1_HF). Kinetic analyses revealed that the antimycotic effects of the leukocyte extract occurred rapidly, with 64% fungal growth inhibition within 3 min of exposure. The molecule(s) responsible for the antimicrobial activities were sensitive to proteases, heat-stable, acid soluble, and in the 1–10 kDa range. These data suggest that alligator leukocytes express cationic peptides that are responsible for their antimicrobial properties.     

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 enrofloxacin after single dose oral and intravenous administration in the African penguin (Spheniscus demersus)

The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy.     

Pharmacokinetics of enrofloxacin after intravenous,intramuscular and oral administration in houbara bustard (Chlamydotis undulata macqueenii)

The in-vitro activity of enrofloxacin against 117 strains of bacteria isolated from bustards was determined. Minimum inhibitory concentrations for 72% of the Proteus spp., E. coli, Salmonella spp. and Klebsiella spp. (n = 61) and for 48% of the Streptococci spp. and Staphylococci spp. (n = 31) were 0.5 μ g/mL. The minimum inhibitory concentration (MIC) of 76% of Pseudomonas spp. (n = 25) was 2 μg/mL. Fourteen strains were resistant to concentrations 128 μg/mL. The elimination half-lives (t½ elim β) (mean± SEM) of 10 mg/kg enrofloxacin in eight houbara bustards (Chlamydotis undulata) were 6.80± 0.79, 6.39± 1.49 and 5.63± 0.54 h after oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) administration, respectively. Enrofloxacin was rapidly absorbed from the bustard gastro-intestinal tract and maximum plasma concentrations of 1.84± 0.16 μg/mL were achieved after 0.66± 0.05 h. Maximum plasma concentration after i.m. administration of 10 mg/kg was 2.75± 0.11 μg/mL at 1.72± 0.19 h. Maximum plasma concentration after i.m. administration of 15 mg/kg in two birds was 4.86 μg/mL. Bioavailability was 97.3± 13.7% and 62.7± 11.1% after i.m. and oral administration, respectively. Plasma concentrations of enrofloxacin 0.5 μg/mL were maintained for at least 12 h for all routes at 10 mg/kg and for 24 h after i.m. administration at 15 mg/kg. Plasma enrofloxacin concentrations were monitored during the first 3 days of treatment in five houbara bustards and kori bustards (Ardeotis kori) with bacterial infections receiving a single daily i.m. injection of 10 mg/kg for 3 days. The mean plasma enrofloxacin concentrations in the clinical cases at 27 and 51 h (3.69 and 3.86 μg/mL) and at 48 h (0.70 μg/mL) were significantly higher compared with the 3 h and 24 h time intervals from clinically normal birds. The maximum plasma concentration (C_max)/MIC ratio was ranked i.v. (10/mg/kg) > i.m. (15 mg/kg) > i.m. (10 mg/kg) > oral (10 mg/kg), but it was only higher than 8:1 for i.v and i.m. administrations of enrofloxacin at 10 mg/kg and 15 mg/kg, respectively, against a low MIC (0.5 μg/mL). A dosage regimen of 10 mg/kg repeated every 12 h, or 15 mg/kg repeated every 24 h, would be expected to give blood concentrations above 0.5 μg/mL and hence provide therapeutic response in the bustard against a wide range of bacterial infections.     

Pharmacokinetics of enrofloxacin after intravenous and intramuscular administration in Angora goats.

Pharmacokinetics and bioavailability of enrofloxacin were determined after single intravenous (IV) and intramuscular (IM) administrations of 5 mg/kg body weight (BW) to 5 healthy adult Angora goats. Plasma enrofloxacin concentrations were measured by high performance liquid chromatography. Pharmacokinetics were best described by a 2-compartment open model. The elimination half-life and volume of distribution after IV and IM administrations were similar (t1/2beta, 4.0 to 4.7 h and Vd(ss),1.2 to 1.5 L/kg, respectively). Enrofloxacin was rapidly (t1/2a, 0.25 h) and almost completely absorbed (F, 90%) after IM administration. Mean plasma concentrations of enrofloxacin at 24 h after IV and IM administration (0.07 and 0.09 microg/mL, respectively) were higher than the minimal inhibitory concentration (MIC) values for most pathogens. In conclusion, once-daily IV and IM administration of enrofloxacin (5 mg/kg BW) in Angora goats may be useful in treatment of infectious diseases caused by sensitive pathogens.     

Evaluation of medetomidine-ketamine anesthesia with atipamezole reversal in American alligators (Alligator mississippiensis).

Sixteen captive and wild-caught American alligators (Alligator mississippiensis), seven juveniles (< or = 1 m total length [TL]; 6.75 +/- 1.02 kg), and nine adults (> or = 2 m TL; 36.65 +/- 38.85 kg), were successfully anesthetized multiple times (n = 33) with an intramuscular (i.m.) medetomidine-ketamine (MK) combination administered in either the triceps or masseter muscle. The juvenile animals required significantly larger doses of medetomidine (x = 220.1 +/- 76.9 microg/kg i.m.) and atipamezole (x = 1,188.5 -/+ 328.1 microg/kg i.m.) compared with the adults (medetomidine, x = 131.1 +/- 19.5 microg/kg i.m.; atipamezole, x = 694.0 +/- 101.0 microg/kg i.m.). Juvenile alligators also required higher (statistically insignificant) doses of ketamine (x = 10.0 +/- 4.9 mg/kg i.m.) compared with the adult animals (x = 7.5 +/- 4.2 mg/kg i.m.). The differences in anesthesia induction times (juveniles, x = 19.6 +/- 8.5 min; adults, x = 26.6 +/- 17.4 min) and recovery times (juveniles, x = 35.4 +/- 22.1 min; adults, x = 37.9 +/- 20.2 min) were also not statistically significant. Anesthesia depth was judged by the loss of the righting, biting, corneal and blink, and front or rear toe-pinch withdrawal reflexes. Recovery in the animals was measured by the return of reflexes, open-mouthed hissing, and attempts to high-walk to the opposite end of the pen. Baseline heart rates (HRs) were significantly higher in the juvenile animals (x = 37 +/- 4 beats/min) compared with the adults (x = 24 +/- 5 bpm). However, RRs (juveniles, x = 8 +/- 2 breaths/min; adults, x = 8 +/- 2 breaths/min) and body temperatures (juveniles, x = 24.1 +/- 1.1 degrees C; adults, x = 25.2 +/- 1.2 degrees C) did not differ between the age groups. In both groups, significant HR decreases were recorded within 30-60 min after MK administration. Cardiac arrhythmias (second degree atrio-ventricular block and premature ventricular contractions) were seen in two animals but were not considered life-threatening. Total anesthesia times ranged from 61-250 min after i.m. injection. Although dosages were significantly different between the age groups, MK and atipamezole provided safe, effective, completely reversible anesthesia in alligators. Drug-dosage differences appear to be related to metabolic differences between the two size-classes, requiring more research into metabolic scaling as a method of calculating anesthetic dosages.     

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 clomipramine and desmethylclomipramine after single-dose intravenous and oral administrations in cats

A cross-over study was performed in six adult spayed cats to determine the pharmacokinetics of clomipramine and its metabolite, desmethylclomipramine (DCMP) after intravenous (0.25 mg/kg) and oral (0.5 mg/kg) single-dose administrations. Plasma clomipramine and DCMP were measured by high-performance liquid chromatography at regular intervals for up to 30 h. Intravenous clomipramine best fit a two-compartmental model yielding an elimination rate constant of 0.037-0.09 h(-1) from which a mean half-life of 12.3 h was calculated. Mean clomipramine AUC(0--infinity) (ngxh/mL), clearance (L/hxkg), V(ss) (L/kg) and MRT (h) values were 652.5, 0.393, 5.0, and 13.5, respectively. Compartmental modeling for clomipramine, after oral administration, and DCMP after both administrations, produced wide parameter estimates and plots of residuals indicated poor goodness of fit. Noncompartmental analysis yielded mean AUC(0--30 h) (ngxh/mL), C(max) (ng/mL) and T(max) (h) of 948.3, 87.5 and 6.2 for clomipramine, and 613.8, 34.8, and 12.8 for DCMP respectively after oral administration. Clomipramine bioavailability was 90%. The present study showed marked pharmacokinetic variability for clomipramine and DCMP through biphasic absorption and potential genetic variability in clomipramine metabolism. It was concluded that population pharmacokinetics would allow better characterization of clomipramine variability that may explain the variability in clinical response noted in cats.     

Pharmacokinetics of doxycycline in sheep after intravenous and oral administration

The pharmacokinetics of doxycycline were investigated in sheep after oral (PO) and intravenous (IV) administration. The IV data were best described using a 2- (n = 5) or 3- (n = 6) compartmental open model. Mean pharmacokinetic parameters obtained using a 2-compartmental model included a volume of distribution at steady-state (V_ss) of 1.759 ± 0.3149 L/kg, a total clearance (Cl) of 3.045 ± 0.5264 mL/kg/min and an elimination half-life (t_1/2β) of 7.027 ± 1.128 h. Comparative values obtained from the 3-compartmental mean values were: V_ss of 1.801 ± 0.3429 L/kg, a Cl of 2.634 ± 0.6376 mL/kg/min and a t_1/2β of 12.11 ± 2.060 h. Mean residence time (MRT_0−∞) was 11.18 ± 3.152 h. After PO administration, the data were best described by a 2-compartment open model. The pharmacokinetic parameter mean values were: maximum plasma concentration (C_max), 2.130 ± 0.950 μg/mL; time to reach C_max (t_max), 3.595 ± 3.348 h, and absorption half-life (t_1/2k01), 36.28 ± 14.57 h. Non-compartmental parameter values were: C_max, 2.182 ± 0.9117 μg/mL; t_max, 3.432 ± 3.307 h; F, 35.77 ± 10.20%, and mean absorption time (MAT_0–∞), 25.55 ± 15.27 h. These results suggest that PO administration of doxycycline could be useful as an antimicrobial drug in sheep.     

Pharmacokinetics of vitacoxib in rabbits after intravenous and oral administration

This study describes the pharmacokinetics of vitacoxib in healthy rabbits following administration of 10 mg/kg intravenous (i.v.) and 10 mg/kg oral. Twelve New Zealand white rabbits were randomly allocated to two equally sized treatment groups. Blood samples were collected at predetermined times from 0 to 36 hr after treatment. Plasma drug concentrations were determined using UPLC‐MS/MS. Pharmacokinetic analysis was completed using noncompartmental methods via WinNonlin^? 6.4 software. The mean concentration area under curve (AUC_last) for vitacoxib was determined to be 11.0 ± 4.37 μg hr/ml for i.v. administration and 2.82 ± 0.98 μg hr/ml for oral administration. The elimination half‐life (T_1/2λz) was 6.30 ± 2.44 and 6.30 ± 1.19 hr for the i.v. and oral route, respectively. The C_max (maximum plasma concentration) and T_max (time to reach the observed maximum (peak) concentration at steady‐state) following oral application were 189 ± 83.1 ng/ml and 6.58 ± 3.41 hr, respectively. Mean residence time (MRT_last) following i.v. injection was 6.91 ± 3.22 and 11.7 ± 2.12 hr after oral administration. The mean bioavailability of oral administration was calculated to be 25.6%. No adverse effects were observed in any rabbit. Further studies characterizing the pharmacodynamics of vitacoxib are required to develop a formulation of vitacoxib for rabbits.