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Objective—To compare pharmacokinetic and pharmacodynamic characteristics of fentanyl citrate after IV or transdermal administration in cats.
Animals—6 healthy adult cats with a mean weight of 3.78 kg.
Procedure—Each cat was given fentanyl IV (25 mg/cat; mean ± SD dosage, 7.19 ± 1.17 mg/kg of body weight) and via a transdermal patch (25 µg of fentanyl/h). Plasma concentrations of fentanyl were measured by use of radioimmunoassay. Pharmacokinetic analyses of plasma drug concentrations were conducted, using an automated curvestripping process followed by nonlinear, leastsquares regression. Transdermal delivery of drug was calculated by use of IV pharmacokinetic data.
Results—Plasma concentrations of fentanyl given IV decreased rapidly (mean elimination half-life, 2.35 ± 0.57 hours). Mean ± SEM calculated rate of transdermal delivery of fentanyl was 8.48 ± 1.7 mg/h (< 36% of the theoretical 25 mg/h). Median steadystate concentration of fentanyl 12 to 100 hours after application of the transdermal patch was 1.58 ng/ml. Plasma concentrations of fentanyl < 1.0 ng/ml were detected in 4 of 6 cats 12 hours after patch application, 5 of 6 cats 18 and 24 hours after application, and 6 of 6 cats 36 hours after application.
Conclusions and Clinical Relevance—In cats, transdermal administration provides sustained plasma concentrations of fentanyl citrate throughout a 5- day period. Variation of plasma drug concentrations with transdermal absorption for each cat was pronounced. Transdermal administration of fentanyl has potential for use in cats for long-term control of pain after surgery or chronic pain associated with cancer. (Am J Vet Res 2000;61:672–677)
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)
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.
Objective—To determine pharmacokinetics, safety, and penetration into interstitial fluid (ISF), polymorphonuclear leukocytes (PMNLs), and aqueous humor of doxycycline after oral administration of single and multiple doses in horses.
Animals—6 adult horses.
Procedure—The effect of feeding on drug absorption was determined. Plasma samples were obtained after administration of single or multiple doses of doxycycline (20 mg/kg) via nasogastric tube. Additionally, ISF, PMNLs, and aqueous humor samples were obtained after the final administration. Horses were monitored for adverse reactions.
Results—Feeding decreased drug absorption. After multiple doses, mean ± SD time to maximum concentration was 1.63 ± 1.36 hours, maximum concentration was 1.74 ± 0.3 μg/mL, and elimination half-life was 12.07 ± 3.17 hours. Plasma protein binding was 81.76 ± 2.43%. The ISF concentrations correlated with the calculated percentage of non-protein-bound drug. Maximum concentration was 17.27 ± 8.98 times as great in PMNLs, compared with plasma. Drug was detected in aqueous humor at 7.5% to 10% of plasma concentrations. One horse developed signs of acute colitis and required euthanasia.
Conclusions and Clinical Relevance—Results suggest that doxycycline administered at a dosage of 20 mg/kg, PO, every 24 hours will result in drug concentrations adequate for killing intracellular bacteria and bacteria with minimum inhibitory concentration ≤ 0.25 μg/mL. For bacteria with minimum inhibitory concentration of 0.5 to 1.0 μg/mL, a dosage of 20 mg/kg, PO, every 12 hours may be required; extreme caution should be exercised with the higher dosage until more safety data are available.
Objective—To determine the pharmacokinetics of butorphanol in cats following IM and buccal transmucosal (BTM) administration, to determine the relative bioavailability of butorphanol following BTM administration, and to extrapolate a plasma concentration associated with antinociception on the basis of existing data from pharmacologic studies of butorphanol in cats.
Animals—6 healthy adult cats.
Procedures—Following IM or BTM butorphanol tartrate (0.4 mg/kg) administration to cats in a 2-way crossover trial, plasma samples were obtained from blood collected via a central venous catheter during a 9-hour period. Plasma butorphanol concentrations were determined by high-performance liquid chromatography.
Results—Data from 1 cat contained outliers and were excluded from pharmacokinetic analysis. Mean ± SD terminal half-life of butorphanol for the remaining 5 cats was 6.3 ± 2.8 hours and 5.2 ± 1.7 hours for IM and BTM administration, respectively. Peak plasma butorphanol concentrations were 132.0 and 34.4 ng/mL for IM and BTM administration, respectively. Time to maximal plasma concentration was 0.35 and 1.1 hours for IM and BTM administration, respectively. Extent of butorphanol absorption was 37.16% following BTM application. On the basis of data from extant pharmacologic studies of butorphanol in cats, mean ± SD duration of antinociception was 155 ± 130 minutes. The estimated plasma concentration corresponding to this time point was 45 ng/mL.
Conclusions and Clinical Relevance—In cats, IM butorphanol administration at 0.4 mg/kg maintained a plasma concentration of > 45 ng/mL for 2.7 ± 2.2 hours, whereas BTM administration at the same dose was not effective at maintaining plasma concentrations at > 45 ng/mL.
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.
Objective—To determine the effect of protein binding on the pharmacokinetics and distribution from plasma to interstitial fluid (ISF) of cephalexin and cefpodoxime proxetil in dogs.
Animals—6 healthy dogs.
Procedures—In a crossover study design, 25 mg of cephalexin/kg or 9.6 mg of cefpodoxime/kg was administered orally. Blood samples were collected before (time 0) and 0.33, 0.66, 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after treatment. An ultrafiltration device was used in vivo to collect ISF at 0, 2, 4, 6, 8, 10, 12, 16, and 24 hours. Plasma and ISF concentrations were analyzed with high-pressure liquid chromatography. Plasma protein binding was measured by use of a microcentrifugation technique.
Results—Mean plasma protein binding for cefpodoxime and cephalexin was 82.6% and 20.8%, respectively. Mean ± SD values for cephalexin in plasma were determined for peak plasma concentration (Cmax, 31.5 ± 11.5 μg/mL), area under the time-concentration curve (AUC, 155.6 ± 29.5 μg•h/mL), and terminal half-life (T½, 4.7 ± 1.2 hours); corresponding values in ISF were 16.3 ± 5.8 μg/mL, 878 ± 21.0 μg•h/mL, and 3.2 ± 0.6 hours, respectively. Mean ± SD values for cefpodoxime in plasma were 33.0 ± 6.9 μg/mL (Cmax), 282.8 ± 44.0 μg•h/mL (AUC), and 5.7 ± 0.9 hours (T1/2); corresponding values in ISF were 4.3 ± 2.0 μg/mL, 575 ± 174 μg•h/mL, and 10.4 ± 3.3 hours, respectively.
Conclusions and Clinical Relevance—Tissue concentration of protein-unbound cefpodoxime was similar to that of the protein-unbound plasma concentration. Cefpodoxime remained in tissues longer than did cephalexin.
Objective—To determine the concentration of doxycycline compounded from doxycycline hyclate tablets into liquid formulations for oral administration in veterinary species and stored for 28 days.
Sample—Doxycycline hyclate tablets (100 mg) crushed and mixed with a 50:50 mixture of syrup and suspension vehicles for oral administration to produce 3 batches each of 2 doxycycline formulations: 33.3 and 166.7 mg/mL.
Procedures—Formulations were stored, protected from light, at room temperature (22° to 26°C [71.6° to 78.8°F]) and at a controlled cold temperature (refrigerated 2° to 8°C [35.6° to 46.4°F]). Doxycycline was extracted from the formulations, and concentration was measured by high-pressure liquid chromatography on days 0 (date of preparation), 1, 4, 7, 14, 21, and 28. Concentrations were compared with those of a US Pharmacopeial Convention reference standard. Formulation quality at each point was also assessed through color change, formulation consistency, and suspension uniformity.
Results—On days 0, 1, 4, and 7, the concentration of each formulation was within 90% to 110% of the reference standard (range, 93% to 109%), which was deemed acceptable. However, doxycycline concentrations had decreased dramatically by day 14 and remained low for the duration of the study period. Doxycycline concentrations on days 14, 21, and 28 were all < 20% (range, 14% to 18%) of the reference standard, and the quality of the formulations decreased as well. No effect of storage temperatures on doxycycline concentration was identified.
Conclusions and Clinical Relevance—The concentration of doxycycline, compounded from commercial tablets in the vehicles evaluated to yield doses of 33.3 and 166.7 mg/mL, cannot be assured beyond 7 days.
Objective—To evaluate the pharmacokinetics and pharmacodynamics of morphine after IV administration as an infusion or multiple doses in dogs by use of a von Frey (vF) device.
Procedure—In the first 2 crossover experiments of a 3-way crossover study, morphine or saline (0.9%) solution was administered via IV infusion. Loading doses and infusion rates were administered to attain targeted plasma concentrations of 10, 20, 30, and 40 ng/mL. In the third experiment, morphine (0.5 mg/kg) was administered IV every 2 hours for 3 doses. The vF thresholds were measured hourly for 8 hours. Plasma concentrations of morphine were measured by highpressure liquid chromatography.
Results—No significant changes in vF thresholds were observed during infusion of saline solution. The vF thresholds were significantly increased from 5 to 8 hours during the infusion phase, corresponding to targeted morphine plasma concentrations > 30 ng/mL and infusion rates ≥ 0.15 ± 0.02 mg/kg/h. The maximal effect (EMAX) was 78 ± 11% (percentage change from baseline), and the effective concentration to attain a 50% maximal response (EC50) was 29.5 ± 5.4 ng/mL. The vF thresholds were significantly increased from 1 to 7 hours during the multiple-dose phase; the EC50 and EMAX were 23.9 ± 4.7 ng/mL and 173 ± 58%, respectively. No significant differences in half-life, volume of distribution, or clearance between the first and last dose of morphine were detected.
Conclusions and Clinical Relevance—Morphine administered via IV infusion (0.15 ± 0.02 mg/kg/h) and multiple doses (0.5 mg/kg, IV, every 2 hours for 3 doses) maintained significant antinociception in dogs. (Am J Vet Res 2005;66:1968–1974)
To determine the pharmacokinetics of levofloxacin following oral administration of a generic levofloxacin tablet and IV administration to dogs and whether the achieved plasma levofloxacin concentration would be sufficient to treat susceptible bacterial infections.
6 healthy adult Beagles.
Levofloxacin was administered orally as a generic 250-mg tablet (mean dose, 23.7 mg/kg) or IV as a solution (15 mg/kg) to each dog in a crossover study design, with treatments separated by a minimum 2-day washout period. Blood samples were collected at various points for measurement of plasma levofloxacin concentration via high-pressure liquid chromatography. Pharmacokinetic analysis was performed with compartmental modeling.
After oral administration of the levofloxacin tablet, mean (coefficient of variation) peak plasma concentration was 15.5 μg/mL (23.8%), mean elimination half-life was 5.84 hours (20.0%), and mean bioavailability was 104% (29.0%). After IV administration, mean elimination half-life (coefficient of variation) was 6.23 hours (14.7%), systemic clearance was 145.0 mL/kg/h (22.2%), and volume of distribution was 1.19 L/kg (17.1%).
CONCLUSIONS AND CLINICAL RELEVANCE
In these dogs, levofloxacin was well absorbed when administered orally, and a dose of approximately 25 mg/kg was sufficient to reach pharmacokinetic-pharmacodynamic targets for treating infections with susceptible Enterobacteriaceae (ie, ≤ 0.5 μg/mL) or Pseudomonas aeruginosa (ie, ≤ 1 μg/mL) according to clinical breakpoints established by the Clinical and Laboratory Standards Institute.