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Author: Mark G. Papich

Abstract

Objective—To determine the pharmacokinetics of ciprofloxacin in dogs, including oral absorption following administration of generic ciprofloxacin tablets.

Animals—6 healthy Beagles.

Procedures—In a crossover study design, ciprofloxacin was administered as a generic tablet (250 mg, PO; mean dose, 23 mg/kg) and solution (10 mg/kg, IV) to 6 dogs. In a separate experiment, 4 of the dogs received ciprofloxacin solution (10 mg/mL) PO via stomach tube (total dose, 250 mg). Blood samples were collected before (time 0) and for 24 hours after each dose. Plasma concentrations were analyzed with high-pressure liquid chromatography. Pharmacokinetic analysis was performed by means of compartmental modeling.

Results—When ciprofloxacin was administered as tablets PO, peak plasma concentration was 4.4 μg/mL (coefficient of variation [CV], 55.9%), terminal half-life (t1/2) was 2.6 hours (CV, 10.8%), area under the time-concentration curve was 22.5 μg•h/mL (CV, 62.3%), and systemic absorption was 58.4% (CV, 45.4%). For the dose administered IV, t1/2 was 3.7 hours (CV, 52.3%), clearance was 0.588 L/kg/h (CV, 33.9%), and volume of distribution was 2.39 L/kg (CV, 23.7%). After PO administration as a solution versus IV administration, plasma concentrations were more uniform and consistent among dogs, with absorption of 71% (CV, 7.3%), t1/2 of 3.1 hours (CV, 18.6%), and peak plasma concentration of 4.67 μg/mL (CV, 17.6%).

Conclusions and Clinical Relevance—Inconsistent oral absorption of ciprofloxacin in some dogs may be formulation dependent and affected by tablet dissolution in the small intestine. Because of the wide range in oral absorption of tablets, the dose needed to reach the pharmacokinetic-pharmacodynamic target concentration in this study ranged from 12 to 52 mg/kg (CV, 102%), with a mean dose of 25 mg/kg, once daily, for bacteria with a minimum inhibitory concentration ≤ 0.25 μg/mL.

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in American Journal of Veterinary Research

Abstract

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 47.89, 98.07, and 94.60%, respectively, and median maximum concentration (Cmax) was 1.61, 2.69, and 2.26 µg/ml, respectively. Median Cmax of the multiple-dose regimen was 2.99 µg/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 ≤ 0.29 µg/ml. (Am J Vet Res 2002; 63:1012–1017)

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in American Journal of Veterinary Research

Abstract

Objective—To compare plasma (total and unbound) and interstitial fluid (ISF) concentrations of doxycycline and meropenem in dogs following constant rate IV infusion of each drug.

Animals—6 adult Beagles.

Procedure—Dogs were given a loading dose of doxycycline and meropenem followed by a constant rate IV infusion of each drug to maintain an 8-hour steady state concentration. Interstitial fluid was collected with an ultrafiltration device. Plasma and ISF were analyzed by high performance liquid chromatography. Protein binding and lipophilicity were determined. Plasma data were analyzed by use of compartmental methods.

Results—Compared with meropenem, doxycycline had higher protein binding (11.87% [previously published value] vs 91.75 ± 0.63%) and lipophilicity (partition coefficients, 0.02 ± 0.01 vs 0.68 ± 0.05). A significant difference was found between ISF and plasma total doxycycline concentrations. No significant difference was found between ISF and plasma unbound doxycycline concentrations. Concentrations of meropenem in ISF and plasma (total and unbound) were similar. Plasma half-life, volume of distribution, and clearance were 4.56 ± 0.57 hours, 0.65 ± 0.82 L/kg, and 1.66 ± 2.21 mL/min/kg, respectively, for doxycycline and 0.73 ± 0.07 hours, 0.34 ± 0.06 L/kg, and 5.65 ± 2.76 mL/min/kg, respectively, for meropenem. The ISF half-life of doxycycline and meropenem was 4.94 ± 0.67 and 2.31 ± 0.36 hours, respectively.

Conclusions and Clinical Relevance—The extent of protein binding determines distribution of doxycycline and meropenem into ISF. As a result of high protein binding, ISF doxycycline concentrations are lower than plasma total doxycycline concentrations. Concentrations of meropenem in ISF can be predicted from plasma total meropenem concentrations. (Am J Vet Res 2003;64:1040–1046)

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in American Journal of Veterinary Research

Abstract

OBJECTIVE To determine pharmacokinetics of posaconazole in dogs given an IV solution, oral suspension, and delayed-release tablet.

ANIMALS 6 healthy dogs.

PROCEDURES Posaconazole was administered IV (3 mg/kg) and as an oral suspension (6 mg/kg) to dogs in a randomized crossover study. Blood samples were collected before (time 0) and for 48 hours after each dose. In an additional experiment, 5 of the dogs received posaconazole delayed-release tablets (mean dose, 6.9 mg/kg); blood samples were collected for 96 hours. Plasma concentrations were analyzed with high-performance liquid chromatography.

RESULTS IV solution terminal half-life (t1/2) was 29 hours (coefficient of variation [CV], 23%). Clearance and volume of distribution were 78 mL/h/kg (CV, 59%) and 3.3 L/kg (CV, 38%), respectively. Oral suspension t1/2 was 24 hours (CV, 42%). Maximum plasma concentration (Cmax) of 0.42 μg/mL (CV, 56%) was obtained at 7.7 hours (CV, 92%). Mean bioavailability was 26% (range, 7.8% to 160%). Delayed-release tablet t1/2 was 42 hours (CV, 25%), with a Cmax of 1.8 μg/mL (CV, 44%) at 9.5 hours (CV, 85%). Mean bioavailability of tablets was 159% (range, 85% to 500%). Bioavailability of delayed-release tablets was 497% (range, 140% to 1,800%) relative to that of the oral suspension.

CONCLUSIONS AND CLINICAL RELEVANCE Absorption of posaconazole oral suspension in dogs was variable. Absorption of the delayed-release tablets was greater than absorption of the oral suspension, with a longer t1/2 that may favor its clinical use in dogs. Administration of delayed-release tablets at a dosage of 5 mg/kg every other day can be considered for future studies.

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in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetics of tramadol, the active metabolite O-desmethyltrcamadol, and the metabolites N-desmethyltramadol and N,O-didesmethyltramadol after oral tramadol administration and to determine the antinociceptive effects of the drug in Greyhounds.

Animals—6 healthy 2- to 3-year-old Greyhounds (3 male and 3 female), weighing 25.5 to 41.1 kg.

Procedures—A mean dose of 9.9 mg of tramadol HCl/kg was administered PO as whole tablets. Blood samples were obtained prior to and at various points after administration to measure plasma concentrations of tramadol and its metabolites via liquid chromatography with mass spectrometry. Antinociceptive effects were determined by measurement of pain-pressure thresholds with a von Frey device.

Results—Tramadol was well tolerated, and a significant increase in pain-pressure thresholds was evident 5 and 6 hours after administration. The mean maximum plasma concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol were 215.7, 5.7, 379.1, and 2372 ng/mL, respectively. The mean area-under-the-curve values for the compounds were 592, 16, 1,536, and 1,013 h·ng/mL, respectively. The terminal half-lives of the compounds were 1.1, 1.4, 2.3, and 3.6 hours, respectively. Tramadol was detected in urine 5 days, but not 7 days, after administration.

Conclusions and Clinical Relevance—Oral tramadol administration yielded antinociceptive effects in Greyhounds, but plasma concentrations of tramadol and O-desmethyltramadol were lower than expected. Compared with the approved dose (100 mg, PO) in humans, a mean dose of 9.9 mg/kg, PO resulted in similar tramadol but lower O-desmethyltramadol plasma concentrations in Greyhounds.

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in American Journal of Veterinary Research

Abstract

Objective—To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs.

Animals—6 healthy adult dogs.

Procedure—Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device.

Results—Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean ± SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 ± 0.07 hours, 0.372 ± 0.053 L/kg, and 6.53 ± 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 ± 0.57 hours. Half-life after SC administration was 0.98 ± 0.21 and 1.31 ± 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%.

Conclusions and Clinical Relevance—Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 µg/mL. (Am J Vet Res 2002;63:1622–1628)

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in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetics of itraconazole after IV or oral administration of a solution or capsules to horses and to examine disposition of itraconazole in the interstitial fluid (ISF), aqueous humor, and polymorphonuclear leukocytes after oral administration of the solution.

Animals—6 healthy horses.

Procedure—Horses were administered itraconazole solution (5 mg/kg) by nasogastric tube, and samples of plasma, ISF, aqueous humor, and leukocytes were obtained. Horses were then administered itraconazole capsules (5 mg/kg), and plasma was obtained. Three horses were administered itraconazole (1.5 mg/kg, IV), and plasma samples were obtained. All samples were analyzed by use of high-performance liquid chromatography. Plasma protein binding was determined. Data were analyzed by compartmental and noncompartmental pharmacokinetic methods.

Results—Itraconazole reached higher mean ± SD plasma concentrations after administration of the solution (0.41 ± 0.13 µg/mL) versus the capsules (0.15 ± 0.12 µg/mL). Bioavailability after administration of capsules relative to solution was 33.83 ± 33.08%. Similar to other species, itraconazole has a high volume of distribution (6.3 ± 0.94 L/kg) and a long half-life (11.3 ± 2.84 hours). Itraconazole was not detected in the ISF, aqueous humor, or leukocytes. Plasma protein binding was 98.81 ± 0.17%.

Conclusions and Clinical Relevance—Itraconazole administered orally as a solution had higher, more consistent absorption than orally administered capsules and attained plasma concentrations that are inhibitory against fungi that infect horses. Administration of itraconazole solution (5 mg/kg, PO, q 24 h) is suggested for use in clinical trials to test the efficacy of itraconazole in horses. (Am J Vet Res 2005;66:1694–1701)

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in American Journal of Veterinary Research

Abstract

Objective—To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals.

Animals—5 clinically normal foals.

Procedure—A 2-dose cross-over trial with IV and oral administration was performed. Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period. Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography.

Results—For IV administration, mean ± SD total area under the curve (AUC0-∞) was 48.54 ± 10.46 µg · h/ml, clearance was 103.72 ± 0.06 ml/kg/h, halflife (t1/2β) was 17.10 ± 0.09 hours, and apparent volume of distribution was 2.49 ± 0.43 L/kg. For oral administration, AUC0-∞ was 58.47 ± 16.37 µg · h/ml, t1/2β was 18.39 ± 0.06 hours, maximum concentration (Cmax) was 2.12 ± 00.51 µg/ml, time to Cmax was 2.20 ± 2.17 hours, mean absorption time was 2.09 ± 0.51 hours, and bioavailability was 42 ± 0.42%.

Conclusions and Clinical Relevance—Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-∞, longer t1/2β, and lower clearance. Concentration of ciprofloxacin was negligible. Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen. (Am J Vet Res 2000;61: 706–709)

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in American Journal of Veterinary Research

Abstract

Objective—To develop a high-performance liquid chromatography (HPLC) assay for cetirizine in feline plasma and determine the pharmacokinetics of cetirizine in healthy cats after oral administration of a single dose (5 mg) of cetirizine dihydrochloride.

Animals—9 healthy cats.

Procedures—Heparinized blood samples were collected prior to and 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after oral administration of 5 mg of cetirizine dihydrochloride to each cat (dosage range, 0.6 to 1.4 mg/kg). Plasma was harvested and analyzed by reverse-phase HPLC. Plasma concentrations of cetirizine were analyzed with a compartmental pharmacokinetic model. Protein binding was measured by ultrafiltration with a microcentrifugation system.

Results—No adverse effects were detected after drug administration in the cats. Mean ± SD terminal half-life was 10.06 ± 4.05 hours, and mean peak plasma concentration was 3.30 ± 1.55 μg/mL. Mean volume of distribution and clearance (per fraction absorbed) were 0.24 ± 0.09 L/kg and 0.30 ± 0.09 mL/kg/min, respectively. Mean plasma concentrations were approximately 2.0 μg/mL or higher for 10 hours and were maintained at > 0.72 μg/mL for 24 hours. Protein binding was approximately 88%.

Conclusions and Clinical Relevance—A single dose of cetirizine dihydrochloride (approx 1 mg/kg, which corresponded to approximately 0.87 mg of cetirizine base/kg) was administered orally to cats. It was tolerated well and maintained plasma concentrations higher than those considered effective in humans for 24 hours after dosing. The half-life of cetirizine in cats is compatible with once-daily dosing, and the extent of protein binding is high.

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in American Journal of Veterinary Research

Abstract

Objective—To characterize pharmacokinetics of voriconazole in horses after oral and IV administration and determine the in vitro physicochemical characteristics of the drug that may affect oral absorption and tissue distribution.

Animals—6 adult horses.

Procedures—Horses were administered voriconazole (1 mg/kg, IV, or 4 mg/kg, PO), and plasma concentrations were measured by use of high-performance liquid chromatography. In vitro plasma protein binding and the octanol:water partition coefficient were also assessed.

Results—Voriconazole was adequately absorbed after oral administration in horses, with a systemic bioavailability of 135.75 ± 18.41%. The elimination half-life after a single orally administered dose was 13.11 ± 2.85 hours, and the maximum plasma concentration was 2.43 ± 0.4 μg/mL. Plasma protein binding was 31.68%, and the octanol:water partition coefficient was 64.69. No adverse reactions were detected during the study.

Conclusions and Clinical Relevance—Voriconazole has excellent absorption after oral administration and a long half-life in horses. On the basis of the results of this study, it was concluded that administration of voriconazole at a dosage of 4 mg/kg, PO, every 24 hours will attain plasma concentrations adequate for treatment of horses with fungal infections for which the fungi have a minimum inhibitory concentration ≤ 1 μg/mL. Because of the possible nonlinearity of this drug as well as the potential for accumulation, chronic dosing studies and clinical trials are needed to determine the appropriate dosing regimen for voriconazole in horses.

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in American Journal of Veterinary Research