Pharmacokinetics of cephalexin in dogs and cats after oral, subcutaneous and intramuscular administration

A three-way crossover study was carried out in 10 dogs and nine cats to establish the pharmacokinetic parameters of the semi-synthetic cephalosporin antibiotic, cephalexin sodium, when administered orally, subcutaneously or intramuscularly. Ten dogs received a subcutaneous or intramuscular injection of 10 mg/kg bodyweight cephalexin or an oral dose of three 50 mg cephalexin tablets; the peak serum concentrations achieved were 24.9, 31.9 and 18.6 micrograms/ml, respectively, and the times taken to reach these peak levels were 1.2, 0.9 and 1.8 hours. Nine cats received either a subcutaneous or intramuscular dose of 0.25 ml cephalexin suspension (approximately 20 mg/kg bodyweight) or an oral dose of one 50 mg tablet; the peak serum concentrations achieved were 54.0, 61.8 and 18.7 micrograms/ml for the subcutaneous, intramuscular and oral administrations respectively, with times to peak concentrations of 1.1, 0.7 and 2.6 hours.     

Plasma concentrations of praziquantel after oral administration of single and multiple doses in loggerhead sea turtles (Caretta caretta)

OBJECTIVE: To determine the pharmacokinetics of praziquantel following single and multiple oral dosing in loggerhead sea turtles. ANIMALS: 12 healthy juvenile loggerhead sea turtles. PROCEDURE: Praziquantel was administered orally as a single dose (25 and 50 mg/kg) to 2 groups of turtles; a multiple-dose study was then performed in which 6 turtles received 3 doses of praziquantel (25 mg/kg, PO) at 3-hour intervals. Blood samples were collected from all turtles before and at intervals after drug administration for assessment of plasma praziquantel concentrations. Pharmacokinetic analyses included maximum observed plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma praziquantel concentration-time curve, and mean residence time (MRTt). RESULTS: Large interanimal variability in plasma praziquantel concentrations was observed for all dosages. One turtle that received 50 mg of praziquantel/kg developed skin lesions within 48 hours of administration. After administration of 25 or 50 mg of praziquantel/kg, mean plasma concentrations were below the limit of quantification after 24 hours. In the multiple-dose group of turtles, mean plasma concentration was 90 ng/mL at the last sampling time-point (48 hours after the first of 3 doses). In the single-dose study, mean Cmax and Tmax with dose were not significantly different between doses. After administration of multiple doses of praziquantel, only MRTt was significantly increased, compared with values after administration of a single 25-mg dose. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of 25 mg of praziquantel/kg 3 times at 3-hour intervals may be appropriate for treatment of loggerhead sea turtles with spirorchidiasis.     

Comparison of pharmacodynamic variables following oral versus transdermal administration of atenolol to healthy cats

OBJECTIVE: To describe the disposition of and pharmacodynamic response to atenolol when administered as a novel transdermal gel formulation to healthy cats. ANIMALS: 7 healthy neutered male client-owned cats. PROCEDURES: Atenolol was administered either orally as a quarter of a 25-mg tablet or as an equal dose by transdermal gel. Following 1 week of treatment, an ECG and blood pressure measurements were performed and blood samples were collected for determination of plasma atenolol concentration at 2 and 12 hours after administration. RESULTS: 2 hours after oral administration, 6 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 579 +/- 212 ng/mL. Two hours following transdermal administration, only 2 of 7 cats reached therapeutic plasma atenolol concentrations with a mean peak concentration of 177 +/- 123 ng/mL. The difference in concentration between treatments was significant. Trough plasma atenolol concentrations of 258 +/- 142 ng/mL and 62.4 +/- 17 ng/mL were achieved 12 hours after oral and transdermal administration, respectively. A negative correlation was found between heart rate and plasma atenolol concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of atenolol at a median dose of 1.1 mg/kg every 12 hours (range, 0.8 to 1.5 mg/kg) in cats induced effective plasma concentrations at 2 hours after treatment in most cats. Transdermal administration provided lower and inconsistent plasma atenolol concentrations. Further studies are needed to find an effective formulation and dosing scheme for transdermal administration of atenolol.     

Pharmacokinetics of amoxycillin and the rate of depletion of its residues in pigs

Six pigs were used in a two-period crossover study to investigate the pharmacokinetics of amoxycillin after single intravenous and oral doses of 20 mg/kg bodyweight. Twelve pigs were used to study the residues of the drug in muscle, kidney, liver and fat after they had received daily oral doses of 20 mg/kg amoxycillin for five days. The mean (sd) elimination half life (t1/2beta) and mean residence time of amoxycillin in plasma were 3.38 (0.30) and 3.54 (0.43) hours, respectively, after intravenous administration and 4.13 (0.50) and 4.47 (0.30) hours, respectively, after oral administration. After oral administration, the maximum plasma concentration (Cmax) was 7.37 (0.42) microg/ml and it was reached after 0.97 (0.29) hours. Six days after the last oral dose, the mean concentration of amoxycillin in the pigs' kidneys was 21.38 ng/g and in the liver it was 12.32 ng/g, but no amoxycillin could be detected in fat or muscle; the concentrations of amoxycillin in edible tissues were less than the European Union maximal residue limit of 50 microg/kg.     

Pharmacokinetics of tinidazole in dogs and cats

Pharmacokinetics of tinidazole in dogs and cats after single intravenous (15 mg/kg) and oral doses (15 mg/kg or 30 mg/kg) were studied in a randomized crossover study. Tinidazole was completely absorbed at both oral dose levels in cats and dogs. Peak tinidazole concentration in plasma was 17.8 micrograms/ml in dogs and 22.5 micrograms/ml in cats after 15 mg/kg p.o. The oral dose of 30 mg/kg resulted in peak levels of 37.9 micrograms/ml in dogs and 33.6 micrograms/ml in cats. The apparent total plasma clearance of the drug was about twofold higher in dogs than in cats, resulting in an elimination half-life that was twice as long in cats (8.4 h) as in dogs (4.4 h). The apparent volume of distribution was 663 ml/kg in dogs and 536 ml/kg in cats. Therapeutic plasma drug concentrations higher than the MIC values of most tinidazole-sensitive bacteria were achieved for 24 h in cats and for 12 h in dogs after a single oral dose of 15 mg/kg. From the pharmacokinetic standpoint tinidazole seems to be well-suited to clinical use in small animal practice.     

Pharmacokinetics of pipemidic acid in chickens after single intravenous and oral dosings

The pharmacokinetics of pipemidic acid after 2 single doses were studied in broiler chickens. Chickens were given single IV and oral doses of 10 and 30 mg of pipemidic acid/kg of body weight. Blood samples were collected over 8 hours after each dose administration. High-pressure liquid chromatography with UV detection was used to determine concentrations in plasma of pipemidic acid. The plasma concentration-time curves after IV administration followed 2-compartment characteristics, rapid initial distribution phase, and a terminal elimination phase. The pharmacokinetic variables differed significantly between single doses of 10 and 30 mg of pipemidic acid/kg. Mean disposition variables were a half-life at alpha phase of 0.06 hours or 0.33 hours, a half-life at beta phase of 1.18 hours or 1.72 hours, a volume of distribution in the central compartment of 0.12 L/kg or 0.31 L/kg, a volume of distribution during the elimination beta phase of 1.64 L/kg or 1.05 L/kg, and a total plasma clearance of 0.97 L/h.kg or 0.41 L/h.kg, for the 10 or 30 mg/kg dose, respectively. After oral administration, the pipemidic acid plasma profile could be adequately described by a 1-compartment model. After the single oral doses of 10 and 30 mg of pipemidic acid/kg, pipemidic acid was absorbed rapidly (time to maximal concentration of 0.31 hours or 0.71 hours) and eliminated with a mean half-life of 0.86 hours or 0.61 hours, respectively. The bioavailability was 39% at 10 mg of pipemidic acid/kg and 61% at 30 mg of pipemidic acid/kg.     

Pharmacokinetics and safety of penciclovir following oral administration of famciclovir to cats

OBJECTIVE: To investigate penciclovir pharmacokinetics following single and multiple oral administrations of famciclovir to cats. ANIMALS: 8 adult cats. PROCEDURES: A balanced crossover design was used. Phase I consisted of a single administration (62.5 mg, PO) of famciclovir. Phase II consisted of multiple doses of famciclovir (62.5 mg, PO) given every 8 or 12 hours for 3 days. Plasma penciclovir concentrations were assayed via liquid chromatography-mass spectrometry at fixed time points after famciclovir administration. RESULTS: Following a single dose of famciclovir, the dose-normalized (15 mg/kg) maximum concentration (C(max)) of penciclovir (350 +/- 180 ng/mL) occurred at 4.6 +/- 1.8 hours and mean +/- SD apparent elimination half-life was 3.1 +/- 0.9 hours. However, the dose-normalized area under the plasma penciclovir concentration-time curve extrapolated to infinity (AUC(0-->)) during phase I decreased with increasing dose, suggesting either nonlinear pharmacokinetics or interindividual variability among cats. Accumulation occurred following multiple doses of famciclovir administered every 8 hours as indicated by a significantly increased dose-normalized AUC, compared with AUC(0-->) from phase 1. Dose-normalized penciclovir C(max)following administration of famciclovir every 12 or 8 hours (290 +/- 150 ng/mL or 780 +/- 250 ng/mL, respectively) was notably less than the in vitro concentration (3,500 ng/mL) required for activity against feline herpesvirus-1. CONCLUSIONS AND CLINICAL RELEVANCE: Penciclovir pharmacokinetics following oral famciclovir administration in cats appeared complex within the dosage range studied. Famciclovir dosages of 15 mg/kg administered every 8 hours to cats are unlikely to result in plasma penciclovir concentrations with activity against feline herpesvirus-1.     

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration

OBJECTIVE: To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. ANIMALS: 7 sexually intact, female, mixed-breed dogs. PROCEDURE: A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. RESULTS: PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.     

Serum and skin concentrations after multiple-dose oral administration of trimethoprim-sulfadiazine in dogs.

Six healthy adult mixed breed dogs were each given 5 oral doses of trimethoprim (TMP)/sulfadiazine (SDZ) at 2 dosage regimens: 5 mg of TMP/kg of body weight and 25 mg of SDZ/kg every 24 hours (experiment 1) and every 12 hours (experiment 2). Serum and skin concentrations of each drug were measured serially throughout each experiment and mean serum concentrations of TMP and SDZ were determined for each drug for 24 hours (experiment 1) and 12 hours (experiment 2) after the last dose was given. In experiment 1, mean serum TMP concentration was 0.67 +/- 0.02 micrograms/ml, and mean skin TMP concentration was 1.54 +/- 0.40 micrograms/g. Mean serum SDZ concentration was 51.1 +/- 12.2 micrograms/ml and mean skin SDZ concentration was 59.3 +/- 9.8 micrograms/g. In experiment 2, mean serum TMP concentration was 1.24 +/- 0.35 micrograms/ml and mean skin TMP concentration was 3.03 +/- 0.54 micrograms/g. Mean serum SDZ concentration was 51.6 +/- 9.3 micrograms/ml and mean skin SDZ concentration was 71.1 +/- 8.2 micrograms/g. After the 5th oral dose in both experiments, mean concentration of TMP and SDZ in serum and skin exceeded reported minimal inhibitory concentrations of TMP/SDZ (less than or equal to 0.25/4.75 micrograms/ml) for coagulase-positive Staphylococcus sp. It was concluded that therapeutically effective concentrations in serum and skin were achieved and maintained when using the manufacturer's recommended dosage of 30 mg of TMP/SDZ/kg (5 mg of TMP/kg and 25 mg of SDZ/kg) every 24 hours.     

Pharmacokinetic characteristics and tissue residues for marbofloxacin and its metabolite N-desmethyl-marbofloxacin in broiler chickens

OBJECTIVES: To determine pharmacokinetic characteristics of marbofloxacin after a single IV and oral administration and tissue residues after serial daily oral administration in chickens. ANIMALS: 40 healthy broiler chickens. PROCEDURE: Two groups of chickens (groups A and B; 8 chickens/group) were administered a single IV and oral administration of marbofloxacin (2 mg/kg). Chickens of group C (n = 24) were given serial daily doses of marbofloxacin (2 mg/kg, PO, q 24 h for 3 days). Plasma (groups A and B) and tissue concentrations (group C) of marbofloxacin and its major metabolite N-desmethyl-marbofloxacin were determined by use of high-performance liquid chromatography. Residues of marbofloxacin and N-desmethylmarbofloxacin were measured in target tissues. RESULTS: Elimination half-life and mean residence time of marbofloxacin in plasma were 5.26 and 4.36 hours after IV administration and 8.69 and 8.55 hours after oral administration, respectively. Maximal plasma concentration was 1.05 microg/ml, and interval from oral administration until maximum concentration was 1.48 hours. Oral bioavailability of marbofloxacin was 56.82%. High concentrations of marbofloxacin and N-desmethyl-marbofloxacin were found in the kidneys, liver, muscles, and skin plus fat 24 hours after the final dose of marbofloxacin; however, marbofloxacin and N-desmethyl-marbofloxacin were detected in only hepatic (27.6 and 98.7 microg/kg, respectively) and renal (39.7 and 69.1 microg/kg, respectively) tissues 72 hours after termination of marbofloxacin treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of pharmacokinetic data obtained in this study reveals that a minimal therapeutic dose of 2 mg/kg, PO, every 24 hours should be appropriate for control of most infections in chickens.     

Residue depletion of thiamphenicol in the sea-bass

The residue depletion of thiamphenicol (TAP) was investigated in the sea-bass (Dicentrarchus labrax) after 5 days' treatment with medicated food at a dose of 15 or 30 mg/kg bw/day. Fish were sampled for blood and muscle + skin from 3 h until 14 days after treatment. Thiamphenicol concentrations were assayed by high performance liquid chromatography. Thiamphenicol concentrations measured 3 h after stopping treatment were 0.77 microg/mL and 0.91 (15 mg/kg dose) or 1.32 microg/mL and 1.47 microg/g (30 mg/kg dose), in plasma and muscle + skin, respectively. After a withdrawal of 3 days, plasma and tissue concentrations were: 0.08 microg/mL and 0.03 microg/g (lower dose) or 0.12 microg/mL and 0.06 microg/g (higher dose), respectively. Thiamphenicol was not detectable either in plasma or in tissues on days 7, 10 and 14 following withdrawal of the medicated food. Based on maximum residue levels (MRL) for TAP in fin fish, established at 50 microg/kg for muscle and skin in natural proportions, a withdrawal period of 5 and 6 days is proposed, after treatment at 15 or 30 mg/kg of TAP with medicated feed pellets, respectively, to avoid the presence of violative residues in the edible tissues of the sea-bass.     

Pharmacokinetics of cetirizine in healthy cats

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 microg/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 microg/mL or higher for 10 hours and were maintained at > 0.72 microg/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.     

The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical doses

This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2‐hydroxypropyl‐β‐cyclodextrin alfaxalone formulation (Alfaxan^®, Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses. First, a prospective two‐period cross‐over study was conducted at single clinical and supraclinical doses. Second, a single group multiple dose study evaluated the effect of maintenance doses. Eight (five female and three male) domestic cats completed the cross‐over experiment and six female cats completed the multiple dose study. In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days. In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus. Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration. Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data. The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 25.1 and 14.8 mL/kg/min respectively. The elimination half lives were 45.2 and 76.6 min respectively. Alfaxalone has nonlinear pharmacokinetics in the cat. Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation. The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect. The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan^® were stable. In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear. At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent. Further, in the un‐premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (i.e., approximately 7 to 8 mg/kg/h).     

Blood and tissue concentrations of trimethoprim following its administration alone and in combination with josamycin.

Following a single oral dose of trimethoprim (10 mg/kg b. wt.) in normal fowls, the highest serum concentration achieved 4 hours post-administration with value of 0.64 microgram/ml. The absorption half-life time was 0.64 hours. The elimination half life was 4.73 hours. During repeated oral administration of 10 mg/kg b. wt., once daily for five consecutive days, trimethoprim peaked in serum, 4 h after each dose. Trimethoprim persisted in all fowl's tissues for 96 hours after stopping of drug administration. After oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) in normal fowls, a maximum serum concentration of trimethoprim was recorded at 2 hours with half-life of absorption (t0.5(ab)) valued 0.74 hour. The elimination half-life (t0.5 beta) was 4.37 hours. During repeated oral administration of josamycin (18 mg/kg b. wt.) and trimethoprim (10 mg/kg b. wt.) once daily for five consecutive days in normal fowls, the highest plasma concentrations of trimethoprim occurred 2 hours post each dose. The daily maximum plasma concentrations during the repeated oral administration of both tested drugs were nearly constant.     

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 of pentoxifylline and its 5-hydroxyhexyl metabolite after oral and intravenous administration of pentoxifylline to healthy adult horses

OBJECTIVE: To determine serum pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite in horses after administration of a single IV dose and after single and multiple oral doses. ANIMALS: 8 healthy adult horses. PROCEDURES: A crossover study design was used with a washout period of 6 days between treatments. Treatments were IV administration of a single dose of pentoxifylline (8.5 mg/kg) and oral administration of generic sustained-release pentoxifylline (10 mg/kg, q 12 h, for 8 days). Blood samples were collected 0, 1, 3, 6, 12, 20, 30, and 45 minutes and 1, 2, 4, 6, 8, and 12 hours after IV administration. For oral administration, blood samples were collected 0, 0.25, 0.5, 0.75, 1, 2, 4, 8, and 12 hours after the first dose and 0, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 hours after the last dose. RESULTS: Elimination of pentoxifylline was rapid after IV administration. After oral administration, pentoxifylline was rapidly absorbed and variably eliminated. Higher serum concentrations of pentoxifylline and apparent bioavailability were observed after oral administration of the first dose, compared with values after administration of the last dose on day 8 of treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, oral administration of 10 mg of pentoxifylline/kg results in serum concentrations equivalent to those observed for therapeutic doses of pentoxifylline in humans. Twice daily administration appears to be appropriate. However, serum concentrations of pentoxifylline appear to decrease with repeated dosing; thus, practitioners may consider increasing the dosage if clinical response diminishes with repeated administration.     

Pharmacokinetics of the antihyperglycemic agent metformin in cats.

OBJECTIVE: To determine the pharmacokinetics of metformin in healthy cats after single-dose IV and oral administration of the drug. ANIMALS: 6 healthy adult ovariohysterectomized cats. PROCEDURE: In a randomized cross-over design study, each cat was given 25 mg of metformin/kg of body weight, IV and orally. Blood and urine samples were collected after drug administration, and concentrations of metformin in plasma and urine were determined by use of high-performance liquid chromatography. RESULTS: Disposition of the drug was characterized by a three-compartment model with a terminal phase half-life of (mean +/- SD) 11.5+/-4.2 hours. Metformin was distributed to a small central compartment of 0.057+/-0.017 L/kg and to 2 peripheral compartments with volumes of distribution of 0.12+/-0.02 and 0.37+/-0.38 L/kg. Steady-state volume of distribution was 0.55+/-0.38 L/kg. After IV administration, 84+/-14% of the dose was excreted unchanged in urine, with renal clearance of 0.13+/-0.03 L/h/kg; nonrenal clearance was negligible (0.02+/-0.02 L/kg). Mean bioavailability of orally administered metformin was 48%. CONCLUSIONS: The general disposition pattern of metformin in cats is similar to that reported for humans. Metformin was eliminated principally by renal clearance; therefore, this drug should not be used in cats with substantial renal dysfunction. CLINICAL RELEVANCE: On the basis of our results, computer simulations indicate that 2 mg of metformin/kg administered orally every 12 hours to cats will yield plasma concentrations documented to be effective in humans.     

Pharmacokinetics and pharmacodynamics of ramipril and ramiprilat in healthy cats

The pharmacokinetics of ramipril and its active metabolite, ramiprilat, was determined in cats following single and repeated oral doses of ramipril (Vasotop^® tablets) (once daily for 9 days) at dose rates of 0.125, 0.25, 0.5 and 1.0 mg/kg. The pharmacodynamic effects were assessed by measuring plasma angiotensin-converting enzyme (ACE) activity. Maximum ramipril concentrations were attained within 30 min following a single dose and declined rapidly (concentrations were below the limit of quantification 4 h after treatment). Peak ramiprilat concentrations were detected at approximately 1.5 h. The apparent terminal half-life ( t _{½ β} ) was ≥20 h irrespective of the dose. Ramiprilat accumulated in plasma (ratio of accumulation 1.3 to 1.9 depending on the dose rate) following repeated administration. Steady-state conditions were attained after the second dose. Excretion was predominant in faeces (87%) and to a lesser extent in urine (11%). The rate and extent of absorption of ramipril as well as its conversion to ramiprilat were not significantly influenced by the presence of food in the gastrointestinal tract. Plasma-ACE activity was almost completely abolished 0.5–2.0 h after treatment, irrespective of the dose rate. Significant inhibition of ACE activity of 54.7 to 82.6% (depending on the dosage) was still present 24 h after treatment. Treatment was well-tolerated in all cats. Ramipril at a dose rate of 0.125 mg/kg once daily produces significant and long-lasting inhibition of ACE activity in healthy cats. The appropriateness of this dosage regime needs to be confirmed in diseased cats.     

Pharmacokinetics and tissue concentrations of azithromycin in ball pythons (Python regius)

OBJECTIVE: To determine pharmacokinetics and tissue concentrations of azithromycin in ball pythons (Python regius) after IV or oral administration of a single dose. ANIMALS: 2 male and 5 female ball pythons. PROCEDURES: Using a crossover design, each snake was given a single dose of azithromycin (10 mg/kg) IV. After a 4-week washout period, each snake was given a single dose of azithromycin (10 mg/kg) orally. Blood samples were collected prior to dose administration and 1, 3, 6, 12, 24, 48, 72, and 96 hours after azithromycin administration. Azithromycin was quantitated by use of liquid chromatography-mass spectrometry. RESULTS: After IV administration, azithromycin had an apparent volume of distribution of 5.69 L/kg and a plasma clearance of 0.19 L/h/kg. Harmonic means for the terminal half-life were 17 hours following IV administration and 51 hours following oral administration. Mean residence times were 37 and 94 hours following IV and oral administration, respectively. Following oral administration, azithromycin had a peak plasma concentration (Cmax) of 1.04 microg/mL, a time to Cmax of 8.4 hours, and a prolonged mean absorption time of 57 hours. Mean oral bioavailability was 77%. Tissue concentrations ranged from 4 to 140 times the corresponding plasma concentration at 24 and 72 hours after azithromycin administration. CONCLUSIONS AND CLINICAL RELEVANCE: Azithromycin is well absorbed and tolerated by ball pythons. On the basis of plasma pharmacokinetics and tissue concentration data, we suggest an azithromycin dosage in ball pythons of 10 mg/kg, orally, every 2 to 7 days, depending upon the site of infection and susceptibil ity of the infective organism.     

Metoclopramide modifies oral cephalexin pharmacokinetics in dogs

The purpose of this study was to investigate whether previous administration of metoclopramide affects cephalexin pharmacokinetics after its oral administration in dogs as well as whether these changes impair its predicted clinical efficacy. Six healthy beagle dogs were included in this study. Oral 25 mg/kg cephalexin monohydrate and intravenous 0.5 mg/kg metoclopramide HCl single doses were administered. Each dog received cephalexin or cephalexin following metoclopramide, with a 2-week washout period. Plasma concentrations of cephalexin were determined by microbiological assay. Cephalexin peak plasma concentration and area under the curve from 0 to infinity significantly increased from 18.77+/-2.8 microg/mL and 82.65+/-10.4 microg.h/mL to 21.88+/-0.8 microg/mL and 113.10+/-20.9 microg.h/mL, respectively, after pretreatment with metoclopramide. No differences between treatments were found for other pharmacokinetic parameters. Pharmacokinetic/pharmacodynamic indices calculated for highly susceptible staphylococci were similar for both experiences. Metoclopramide pretreatment may have increased cephalexin absorption by affecting its delivery to the intestine, and/or enhancing intestinal transporter PEPT1 function. Neither difference in the efficacy of cephalexin nor an increase in toxicity is expected as a result of this modification. Consequently, no dose adjustment is required in cephalexin-treated patients pretreated with metoclopramide.