Levamisole pharmacokinetics and bioavailability in dogs

Levamisole was given intravenously and orally (with and without food) to six dogs. All dogs reacted adversely to intravenous dosage and one died. For the remaining five, intravenous data fitted a one compartment model with first order elimination and a mean half-time of elimination of 1.8 hours. In fasting dogs drug absorption from the gut was rapid and the mean fraction absorbed (F) was 0.64. When levamisole was given with food, drug bioavailability was impaired, as absorption was slowed and possibly reduced (F = 0.49). The effect of ingesta on bioavailability of levamisole could affect treatment efficacy and side effects.     

The pharmacokinetics and bioavailability of acepromazine in the plasma of dogs]

Acepromazine is extensively used in veterinary practice. In dogs, it is used mainly as a preanaesthetic and sedative agent, without the knowledge of pharmacokinetic data in this species. We studied the disposition both after oral and intravenous administration. It was shown, that the sedative effect after an oral dose of 1.3-1.5 mg/kg lasted for about 4 hours. The elimination was slower after oral administration (half-life 15.9 h) than after i. v. injection (half-life 7.1 h). The bioavailability of the orally administered drug formulation averaged 20%. The calculation of the pharmacokinetic parameters was performed computer-aided, using conventional compartmental analysis and non-compartmental statistical moment analysis and the results were compared.     

Effect of ofloxacin on theophylline pharmacokinetics at clinical dosage in dogs

We examined the effects of ofloxacin (OFX) and norfloxacin (NFX) on theophylline (TP) pharmacokinetics in dogs. OFX, as a noncompetitive and mechanism-based inhibitor, and NFX, as a noncompetitive inhibitor, were orally administered (5 mg/kg) for a single dose or multiple doses (12 hourly for 3 days). TP (5 mg/kg, i.v) was injected at 2 h after the final dose of the fluoroquinolones (FQs). The same dose of TP was injected (i.v) 3 weeks before the start of FQs treatment for control. Multiple doses of OFX significantly reduced the total body clearance (Cl(B)) of TP from 0.117 to 0.085 L/h/kg, although a single dose did not change it. Neither a single dose nor multiple doses of NFX changed the TP pharmacokinetics. Plasma NFX concentrations increased after multiple doses. Those of OFX also increased but were still two orders of magnitude below the K(i) for noncompetitive inhibition of CYP1A in dogs. Time-dependent reduction in Cl(B) of TP suggests that mechanism-based inhibition of OFX was the major mode to decrease Cl(B) of TP. The mechanism-based inhibition may result in substantial inhibition of CYP1A activities in clinical conditions.     

Pharmacokinetics of an extended-release theophylline product in cats

OBJECTIVE: To evaluate the pharmacokinetics of a brand of extended-release theophylline tablets and capsules in healthy cats. DESIGN: Randomized 3-way crossover study. ANIMALS: 6 healthy cats. PROCEDURES: A single dose of aminophylline (10 mg/kg [4.5 mg/lb], IV), a 100-mg extended-release theophylline tablet, or a 125-mg extended-release theophylline capsule was administered to all cats. Plasma samples were collected via preplaced central catheters throughout a 36-hour period. Plasma samples were frozen until analyzed by use of a fluorescence polarization monoclonal immunoassay. RESULTS: All cats tolerated drug administration and plasma collection with no adverse effects. Peak concentrations were reached for both orally administered products between 8 and 12 hours after administration. Bioavailability was excellent. Plasma concentrations were within the human therapeutic concentration of 5 to 20 microg/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Daily administration of the brand of theophylline tablets and capsules used in this study at 15 mg/kg (6.8 mg/lb) and 19 mg/kg (8.6 mg/lb), respectively, maintained plasma concentrations within the desired therapeutic range in healthy cats.     

Clindamycin bioavailability and pharmacokinetics following oral administration of clindamycin hydrochloride capsules in dogs

Oral bioavailability and pharmacokinetic behaviour of clindamycin in dogs was investigated following intravenous (IV) and oral (capsules) administration of clindamycin hydrochloride, at the dose of 11 mg/kg BW. The absorption after oral administration was fast, with a mean absorption time (MAT) of 0.87+/-0.40 h, and bioavailability was 72.55+/-9.86%. Total clearance (CL) of clindamycin was low, after both IV and oral administration (0.503+/-0.095 vs. 0.458+/-0.087 L/h/kg). Volume of distribution at steady-state (IV) was 2.48+/-0.48 L/kg, indicating a wide distribution of clindamycin in body fluids and tissues. Elimination half-lives were similar for both routes of administration (4.37+/-1.20 h for IV, vs. 4.37+/-0.73 h for oral). Serum clindamycin concentrations following administration of capsules remained above the MICs of very susceptible microorganisms (0.04-0.5 microg/mL) for 12 or 10 h, respectively. Time above the mean inhibitory concentration (MIC) is considered as the index predicting the efficacy of clindamycin (T(>MIC) must be at least 40-50% of the dosing interval), so a once-daily oral administration of 11 mg/kg BW of clindamycin can be considered therapeutically effective. For less susceptible bacteria (with MICs of 0.5-2 microg/mL) the same dose should be given but twice daily.     

Pharmacokinetics of two once-daily parenteral cephalexin formulations in dogs

The aims of this study were to describe and compare the pharmacokinetic profiles and T(>MIC90) of two commercially available once-daily recommended cephalexin formulations in healthy adult dogs administered by the intramuscular (i.m.) route. Six beagle dogs received a 10 mg/kg dose of an 18% parenteral suspension of cephalexin of laboratory A (formulation A) and laboratory B (formulation B) 3 weeks apart. Blood samples were collected in predetermined times after drug administration. The main pharmacokinetic parameters were (mean +/- SD): AUC((0-infinity)), 72.44 +/- 15.9 and 60.83 +/- 13.2 microg.h/mL; C(max), 10.11 +/- 1.5 and 8.50 +/- 1.9 microg/mL; terminal half-life, 3.56 +/- 1.5 and 2.57 +/- 0.72 h and MRT((0-infinity)), 5.86 +/- 1.5 and 5.36 +/- 1.2 h for formulations A and B, respectively. T(>MIC90) was 63.1 +/- 14.7 and 62.1 +/- 14.7% of the dosing interval for formulations A and B, respectively. Median (range) for t(max) was 2.0 (2.0-3.0) h and 3.0 (2.0-4.0) for formulations A and B, respectively. Geometric mean ratios of natural log-transformed AUC((0-infinity)) and C(max) and their 90% confidence intervals (CI) were 0.84 (0.72-0.98) and 0.83 (0.64-1.07), respectively. The plasma profiles of cephalexin following the administration of both formulations were similar. No statistical differences between pharmacokinetic parameters or T(>MIC90) were observed, however, bioequivalence between both formulations could not be demonstrated, as lower 90% CI failed to fell within the selected range of 80-125% for bioequivalence.     

Pharmacokinetics of cephalexin from two oral formulations in dogs

Six beagle dogs were treated with cephalexin-monohydrate from 2 oral formulations (Rilexine tablets and Cefaseptin dragees, respectively) in a dosage of 25 mg/kg and plasma concentrations of cephalexin were measured over 8 hours. After solid phase extraction of the samples, cephalexin was determined by high pressure liquid chromatography with UV detection. After administration, Cephalexin was absorbed rapidly and mean maximum plasma concentrations of 30.9 and 27.9 micrograms/ml, respectively, were acquired after approximately 1.6 hours. Minimal inhibitory concentrations of < or = 6.25 micrograms/ml for in vitro sensitive bacteria were maintained for about 5 hours. Cephalexin from the tested preparations reached a mean area under the plasma concentration-time curve of 115.3 and 102.4 micrograms.h/ml, respectively. The plasma concentration decreased rapidly with a mean half life period of 1.4 hours in average. The other calculated pharmacokinetic parameters were also in the area of the data for dogs stated in the literature. There was no clear difference in the pharmacokinetics of both products, especially the bioavailability. Furthermore, both formulations were well tolerated clinically.     

Pharmacokinetics and bioavailability of theophylline in horses

The pharmacokinetics and bioavailability of theophylline in horses were investigated following both intravenous and intragastric administration of aminophylline solutions at doses corresponding to 15 and 10 mg/kg theophylline base. A rapid distributive phase with a half-life of approximately 15-30 min was followed by a slower elimination half-life averaging 15-17 h. The apparent volume of distribution averaged 850-900 ml/kg. Theophylline, administered as aminophylline solution, was both rapidly and completely absorbed from the equine digestive tract. Based on the bioavailability and disposition kinetics of theophylline, an intragastric dosage regimen for aminophylline consisting of the administration of 5 mg/kg at 12 h intervals would be expected to maintain plasma theophylline concentrations within the therapeutic range.     

Sustained-release theophylline pharmacokinetics in the cat

Theophylline was administered in a three-way crossover design study to six cats intravenously (Aminophylline USP, Invenex Laboratories, Chagrin Falls, OH) and orally as two sustained-release formulations (Slo-bid Gyrocaps (SB), William H. Rorer, Inc., Fort Washington, PA; Theo-Dur Tablets (TD), Key Pharmaceuticals, Miami, FL). Values were determined for mean residence time (SB = 19.4 +/- 3.2 h; TD = 15.8 +/- 4.8 h), mean absorption time (SB = 8.0 +/- 2.3 h; TD = 4.8 +/- 2.3 h), absolute bioavailability (SB = 82 +/- 27%; TD = 76 +/- 38%), and time to peak plasma concentrations (SB = 8 h; TD = 8 h). After normalization to a dose of 25 mg/kg, the average peak plasma concentrations were also predicted (SB = 10.5 +/- 3.4 micrograms/ml; TD = 14.3 +/- 6.7 micrograms/ml). Slo-bid was predicted to provide the least peak:trough fluctuation in theophylline concentrations. Slo-bid and Theo-Dur appear to have pharmacokinetic characteristics which, if given once-daily, would maintain plasma theophylline concentrations of 5-20 micrograms/ml in the cat.     

Evaluation of the pharmacokinetics and bioavailability of intravenously and orally administered amiodarone in horses

OBJECTIVE: To determine the clinical effects and pharmacokinetics of amiodarone after single doses of 5 mg/kg administered orally or intravenously. ANIMALS: 6 healthy adult horses. PROCEDURE: In a cross over study, clinical signs and electrocardiographic variables were monitored and plasma and urine samples were collected. A liquid chromatography-mass spectrometry method was used to determine the percentage of protein binding and to measure plasma and urine concentrations of amiodarone and the active metabolite desethylamiodarone. RESULTS: No adverse clinical signs were observed. After IV administration, median terminal elimination half-lives of amiodarone and desethylamiodarone were 51.1 and 75.3 hours, respectively. Clearance was 0.35 L/kg x h, and the apparent volume of distribution for amiodarone was 31.1 L/kg. The peak plasma desethylamiodarone concentration of 0.08 microg/mL was attained 2.7 hours after IV administration. Neither parent drug nor metabolite was detected in urine, and protein binding of amiodarone was 96%. After oral administration of amiodarone, absorption of amiodarone was slow and variable; bioavailability ranged from 6.0% to 33.7%. The peak plasma amiodarone concentration of 0.14 microg/mL was attained 7.0 hours after oral administration and the peak plasma desethylamiodarone concentration of 0.03 microg/mL was attained 8.0 hours after administration. Median elimination half-lives of amiodarone and desethylamiodarone were 24.1 and 58.6 hours, respectively. CONCLUSION AND CLINICAL RELEVANCE: Results indicate that the pharmacokinetic distribution of amiodarone is multicompartmental. This information is useful for determining treatment regimens for horses with arrythmias. Amiodarone has low bioavailability after oral administration, does not undergo renal excretion, and is highly protein-bound in horses.     

Comparison of the pharmacokinetics of two formulations of hydroxyethyl starch in healthy horses

A lower molecular weight and molar substitution formulation (130/0.4) of hydroxyethyl starch solution has been shown to have a more sustained effect on COP and similar hemodynamic effects as a higher molecular weight and molar substitution formulation (600/0.75) in healthy horses. In humans, these pharmacodynamic characteristics are coupled with more rapid clearance and decreased adverse coagulation effects and accumulation. The objective of this study was to determine and compare the pharmacokinetics of these two formulations in horses. Eight healthy horses were given a 10 mL/kg bolus of each formulation (600/0.75 and 130/0.4) of hydroxyethyl starch solution in a randomized crossover design. Blood was collected, and plasma was harvested for plasma levels over 24 h. Pharmacokinetic parameters for each horse were estimated from a noncompartmental analysis. Treatment with 600/0.75 resulted in a higher initial plasma concentration (C₀), systemic half‐life (t_1/2), and overall drug exposure (AUC_0–inf) in addition to decreased elimination rate (β), volume of distribution (Vd), and clearance (CL), compared to treatment with 130/0.4 (P < 0.001). The pharmacokinetic findings combined with previous pharmacodynamics findings suggest that 130/0.4 can provide similar benefits to 600/0.75 with a lower risk of accumulation in the circulation.     

Comparative pharmacokinetics, bioavailability and renal clearance of five parenteral oxytetracycline-20% formulations in dairy cows

Oxytetracycline (OTC) concentrations on plasma and milk of dairy cows were determined following a single intramuscular injection of five oxytetracycline-20% formulations at a dosage of approximately 10 mg/kg. For obtaining pharmacokinetic reference parameters, one 10% OTC formulation was administered intravenously. The five 20% formulations were compared and evaluated pharmacokinetically with respect to absorption rate, peak plasma and milk OTC concentrations, biological half-life, and relative bioavailability. The mean maximum plasma OTC concentrations varied between 4.5 and 6.8 micrograms/ml and were achieved between 5 and 10 h p.i., depending on the formulation involved. The mean maximum milk concentrations, ranging from 1.12 to 1.92 micrograms/ml, were achieved 12 to 24 h p.i. A plasma OTC concentration exceeding 0.5 microgram/ml was maintained for 48 h to 70 h, and in milk for 33 to 49 h, depending on the formulation involved. Formulations exhibiting the lowest clinically noticeable irritation showed the highest peak plasma OTC concentrations and the best bioavailability. Among the formulations the calculated withholding periods for milk were in the range of 3 to 4 days and for edible tissues of 9 to 14 days. The OTC and creatinine clearances were significantly correlated to each other and to the urinary flow. OTC was excreted predominantly by glomerular filtration, partly by tubular secretion minus urogenital (distal renal tubuli and bladder) reabsorption.     

Contrast between the pharmacokinetics of two formulations of cephalexin after intramuscular administration in cattle

Two commercial formulations of cephalexin were administered intramuscularly to five heifers and five bulls in a balanced crossover design. Statistically significant and clinically important differences were detected between the two formulations of cephalexin. These results suggest that 24 h dose intervals would be appropriate with only one of the formulations and that the recommended dose rates for each product may need to be reviewed.     

Bioavailability of four slow-release theophylline formulations in the Beagle dog

Theophylline was administered to six Beagles intravenously (Aminophyllin Injectable, Searle Laboratories) and orally as four sustained-release formulations (Choledyl -SA Tablets, Parke-Davis; Theo-Dur Tablets, Key Pharmaceuticals; Theo-24 Capsules, Searle Laboratories, and Slo-bid Gyrocaps, William H. Rorer, Inc.). Values were determined for mean residence time, mean absorption time, absolute bioavailability, time to peak plasma concentration, and peak plasma concentration normalized to a theophylline dose of 20 mg/kg. In this order the values found for each formulation were: Choledyl (10.2 +/- 1.8 h, 2.8 +/- 2.2 h, 63 +/- 10%, 3.9 +/- 1.0 h, 10 +/- 1.1 micrograms/ml), Theo-Dur (12.1 +/- 5.2 h, 4.9 +/- 5.3 h, 76 +/- 18% 4.7 +/- 3.1 h, 12 +/- 3.7 micrograms/ml), Theo-24 (15.6 +/- 8.9 h, 8.1 +/- 8.4 h, 30 +/- 16%, 3.6 +/- 1.7 h, 3.5 +/- 1.3 micrograms/ml), and Slo-bid (11.9 +/- 1.9 h, 4.4 +/- 1.3 h, 60 +/- 9%, 4 +/- 1.1 h, 8.6 +/- 0.8 micrograms/ml). Choledyl, Theo-Dur and Slo-bid appear to have absorption characteristics which, if given twice daily, would maintain therapeutic plasma concentrations of theophylline between 10 and 20 micrograms/ml in the dog. Of these, Theo-Dur was predicted to provide the least peak:trough fluctuation in theophylline plasma concentrations.     

Comparison of the pharmacokinetic profiles of two different amphotericin B formulations in healthy dogs

This study was conducted to compare the pharmacokinetic profiles of conventional (Fungizone^®) and liposomal amphotericin B (AmBisome^®) formulations in order to predict their therapeutic properties, and evaluate their potential differences in veterinary treatment. For this purpose, twelve healthy mixed breed dogs received both drugs at a dose of 0.6 mg/kg by intravenous infusion over a 4‐min period in a total volume of 40 ml. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72 and 96 hr after dosing, and concentrations of drug in plasma were determined by high‐performance liquid chromatography (HPLC). Pharmacokinetics was described by a two‐compartment model. Although both formulations were administered at the same doses (0.6 mg/kg), the plasma pharmacokinetics of liposomal amphotericin B differed significantly from those of amphotericin B deoxycholate in healthy dogs (p < .05). Liposomal amphotericin B showed markedly higher peak plasma concentrations (approximately ninefold greater) and higher area under the plasma concentration curve values (approximately 14‐fold higher) compared to conventional formulation. It is concluded that AmBisome^® reached higher plasma concentration and lower distribution volume and had a longer half‐life compared to Fungizone^®, and therefore, AmBisome^® is reported to be an appropriate and effective choice for the treatment of systemic mycotic infections in dogs.     

The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs

Pimobendan is a benzimidazole‐pyridazinone derivative, marketed as a racemic mixture for the management of canine heart failure. Pharmacokinetics of the enantiomers of pimobendan and its oral bioavailability have not been described in dogs. The aim of this study was to describe pharmacokinetics of three formulations of pimobendan in healthy dogs: the licensed capsule product, and novel liquid and intravenous formulations. A three‐period, nested randomized two‐treatment crossover design was used. Pimobendan was administered p.o. at 0.25 and i.v. at 0.125 mg/kg. Blood and plasma samples were analysed by liquid chromatography–mass spectrometry. Noncompartmental modelling was used to describe the pharmacokinetics. Parameters were compared between formulations using a general linear model. Bioequivalence of the oral formulations was tested using CI90 for AUC_(0–∞) and C_max. Bioavailability of pimobendan after oral dosing was 70%. Liquid and capsule formulations were bioequivalent only for AUC. The positive enantiomer of pimobendan (PE) had a larger volume of distribution than the negative enantiomer (NE) (281 ± 48 vs. 215 ± 68 mL/kg; P = 0.003) and a shorter half‐life (21.7 vs. 29.9 min; P = 0.004). The NE was distributed more quickly than the PE into blood cells. Enantiomers of pimobendan have differing absorption, distribution and elimination. The pharmacokinetics of pimobendan in healthy dogs was described.     

Pharmacokinetic studies of theophylline in dogs

The pharmacokinetics of theophylline were investigated in dogs following intravenous, single oral, and multiple oral doses of aminophylline. Mean half-life ( t _1/2) of theophylline following single intravenous administration was 5.7 h and the apparent specific volume of distribution ( V'd area) was 0.82 litre/kg. The bioavailability of theophylline was high (91%) following oral administration of aminophylline tablets and the absorption half-life ( t _{1/2 ab}) was 0.4 h.
Theophylline plasma concentrations observed following repeated oral administration of aminophylline tablets were somewhat greater than predicted. This suggests that theophylline plasma concentrations should be monitored and the dosage regimen individually adjusted in critically ill animals.     

Voluntary acceptance and consumption of two oral ciclosporin formulations in dogs: two randomised,controlled studies

Background

Atopic dermatitis (AD) is the most common canine allergic skin disease and can significantly affect the quality of life of affected dogs. Treating canine AD with ciclosporin has been a subject of great interest in recent years. Many studies have provided substantial evidence of ciclosporin efficacy and safety in canine AD management, and for several years ciclosporin has been recognised as a major component of canine AD multimodal therapy. As a chronic condition, canine AD requires life-long medical management and treatment success relies in large part on product ease of administration. Two studies were conducted to assess the comparative voluntary acceptance and consumption of Cyclavance® (Virbac), a new oral liquid formulation of ciclosporin, and Atopica® (Novartis) either added to a small quantity of kibbles (study 1) or administered directly into the dog’s mouth (study 2).

Results

Over the course of the two studies 70 dogs assessed each of the ciclosporin formulations and 320 individual tests were performed for each tested product. Immediate prehension (in less than 2 seconds) occurred significantly more often with Cyclavance® (90.6% of the tests) than with Atopica® (14.4% of the tests) when products were mixed with 30 grams of dry food (p < 0.001). Moreover, Cyclavance® was significantly more often easily accepted than Atopica® (99.3% vs 27.1% of the tests, respectively) when products were administered directly into the dogs’ mouth (p < 0.0001). Cyclavance® was also more often totally consumed (98.3% of the tests) than Atopica® (2.2% of the tests) when mixed with a small amount of food (p < 0.001). However, both products were totally consumed once administered directly into the dogs’ mouth.

Conclusions

By facilitating cicloporin administration and consumption, Cyclavance® liquid formulation offers an interesting alternative to capsules that may improve dosing compliance and therefore the ability to benefit from the therapeutic effects in the long-term treatment of canine AD.     

Comparison of bioavailability of two chloramphenicol preparations in dogs after intramuscular injection.

Aqueous chloramphenicol glycinate was compared with propylene glycol solution of chloramphenicol after equivalent intramuscular doses (22 mg/kg) were given to 10 normal, healthy dogs in a crossover study. Duration and magnitude of plasma concentrations of chloramphenicol were significantly longer and higher with the glycinate than with the propylene glycol solution.