Distribution and elimination of clenbuterol in tissues and fluids of calves following prolonged oral administration at a growth-promoting dose

A pharmacokinetic study is described in which Friesian calves (n = 30) were treated orally with clenbuterol at 10 times the therapeutic dose. The study was designed to establish the distribution and elimination of clenbuterol from edible tissues, the major compartments of the eye and body fluids. Animals (n= 24) were dosed (10 μg/kg body weight) twice daily with clenbuterol for 21 days and slaughtered in groups of five (one untreated control animal per group) at 6 h and 1, 2, 4, 8 and 16 days after cessation of treatment At slaughter, samples of diaphragm muscle, liver, kidney, bile, urine and both eyes were obtained. One of the eyes was separated into constituent tissues: aqueous humour, vitreous humour, comea, lens, retina (without pigmented epithelium), choroid (with pigmented retinal epithelium; choroid/PRE) and sclera. All samples were stored at -20°C. Clenbuterol concentrations were higher in liver than kidney, bile and urine from day 2 of withdrawal onwards. Concentrations in choroid/PRE were at least 10 times higher than in liver at all periods following cessation of treatment and 52 times higher 16 days after treatment The concentrations of clenbuterol in the constituent tissues of the eye were in the order choroid/PRE > comea > sclera > retina > aqueous humour/vitreous humour ≥ lens. Concentrations of clenbuterol in choroid/PRE taken from eyes frozen whole were generally lower than those in choroid/PRE separated before storage. Choroid/PRE stored by either method contained clenbuterol at more than 100 ng/g 16 days following cessation of treatment These data suggest that analysis of choroid taken at the abattoir would provide reliable surveillance information on the use or abuse of clenbuterol within the slaughter population. It is proposed that liver samples taken concurrently could be used in the event of a positive result from choroid/PRE analysis to indicate whether the maximum residue limit for edible tissues has been exceeded.     

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.     

Pharmacokinetics of marbofloxacin in dogs after oral and parenteral administration

Six dogs were treated with a single intravenous (i.v.) dose (2 mg/kg) of marbofloxacin, followed by single oral (p.o.) doses of marbofloxacin at 1, 2 and 4 mg/kg, according to a three-way crossover design. The same experimental design was used for the subcutaneous (s.c.) route. In addition, a long-term trial involving eight dogs given oral doses of marbofloxacin at 2, 4 and 6 mg/kg/day for thirteen weeks was carried out. Plasma and urine samples were collected during the first two trials, plasma and skin samples were collected after the second of these trials. Plasma, urine and skin concentrations of marbofloxacin were determined by a reverse phase liquid chromatographic method. Mean pharmacokinetic parameters after i.v. administration were the following: t1/2β=12.4h; Cl _B= 0.10 L/h.kg; V _area= 1.9 L/kg. The oral bioavailability of marbofloxacin was close to 100% for the three doses. At 2 mg/kg, C _max of 1.4 μg/mL was reached at t _max of 2.5 h. Mean AUC and C _max values had a statistically significant linear relationship with the doses administered. About 40% of the administered dose was excreted in urine as unchanged parent drug. After s.c. administration, the calculated parameters were close to those obtained after oral administration, except t _max (about 1 h) which was shorter. The mean skin to plasma concentration ratio after the long-term trial was 1.6, suggesting good tissue penetration of marbofloxacin.     

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.     

Disposition of clorazepate in dogs after single- and multiple-dose oral administration

Clorazepate dipotassium was administered orally to 8 healthy dogs at a dosage of 2 mg/kg of body weight, q 12 h, for 21 days. Serum disposition of nordiazepam, the principle metabolite of clorazepate, was determined after the first and last dose of clorazepate. Disposition variables were analyzed by use of model-independent pharmacokinetics by the predictive equations method and the trapezoidal rule method. Complete blood counts, serum chemical analyses, and urinalyses were performed before administration of clorazepate and at 10 and 21 days after administration of clorazepate. Maximal nordiazepam concentrations ranged from 446 to 1,542 ng/ml (814 +/- 334 ng/ml), at 59 to 180 minutes (97.9 +/- 42.0 minutes) after a single oral dose of clorazepate. Maximal nordiazepam concentrations ranged from 927 to 1,460 ng/ml (1,308 +/- 187.6 ng/ml), at 120 to 239 minutes (153 +/- 57.9 minutes) after multiple oral doses of clorazepate. Serum disposition was significantly altered after multiple doses of clorazepate. Using data determined by the predictive equations method, the mean residence time after multiple doses (712 +/- 214 minutes) was longer (P less than 0.05) than after a single dose (527 +/- 95.8 minutes). Oral volume of distribution after multiple doses of clorazepate (1.76 +/- 0.647 L/kg) was smaller (P less than 0.02) than after a single dose (3.18 +/- 1.52 L/kg). Oral clearance after multiple doses of clorazepate (3.09 +/- 0.726 ml/min/kg) was less (P less than 0.001) than after a single dose (6.54 +/- 2.15 ml/min/kg). Absorption half-life after multiple doses (72 minutes) was longer (P less than 0.01) than after a single dose (33 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of chloramphenicol absorption in calves after oral, intra-ruminal and intra-abomasal administration

The mechanisms responsible for the rapid decline of chloramphenicol plasma levels after oral administration in young calves during their first weeks of life were investigated. Chloramphenicol was administered by stomach tube, to four 2 week old calves on three consecutive days at a dose of 50 mg/kg. The plasma levels increased daily to a peak value on the third day. The minimum therapeutic concentration of 5 μg/ml, however, was barely obtained. Simultaneous estimation of the ruminal contents showed a parallel increase in chloramphenicol concentration. Thus it can be assumed that there is an inefficient absorption of chloramphenicol from the forestomachs of young calves. Chloramphenicol was not metabolized by the ruminal contents until the calves were 9 weeks old. Finally chloramphenicol was administered to 7 week old calves by the intra-abomasal route, intraruminal route and by mouth. Only with the intra-abomasal method could a therapeutically effective level be reached. This indicates that the rapid decline of chloramphenicol plasma levels in calves during their first weeks of life could be attributed to the delayed reticulo-rumen emptying and to inefficient absorption from the forestomachs.     

Pharmacokinetics of oestriol after repeated oral administration to dogs

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1-7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before (C(trough)) and 1 h after dosing (C(t=1h)). During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, C(max) and t(max), were determined from the plasma concentration-time curves using non-compartmental methods. The between animal variation in C(max) and the AUC was high. Individual values of the C(max) varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC(0-24h) from 789 pg x h/ml (day 1) to 5718 pg x h/ml (day 7). t(max) occurred within 1 h. The mean C(trough) value was slightly above the pre-treatment level ( 38+/-2 pg/ml vs. 18+/-5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. C(max) and C(trough) did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration-time curve around 8-12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC(0-24h) was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations.     

Residue depletion of decoquinate in chicken tissues after oral administration

Wang, Z.‐Y., Cai, C.‐Y., Chang, X.‐H., Fei, C.‐Z., Qiu, M.‐Q., Jiang, S.‐X., Xue, F.‐Q., Zhang, L.‐F. Residue depletion of decoquinate in chicken tissues after oral administration. J. vet. Pharmacol. Therap.  36 , 116–121. A rapid, sensitive, and reliable high‐performance liquid chromatography tandem mass spectrometry (LC‐MS/MS) method was developed and validated for the analysis of decoquinate in chicken tissues. The compounds were extracted using acetonitrile by liquid–liquid extraction (LLE) and purified with an Oasis^? HLB solid‐phase extraction (SPE) cartridge. Chromatographic separation was performed on an XTerra C₁₈ reversed‐phase column with a mobile phase of water containing 0.1% formic acid and acetonitrile. The analyte was detected by tandem quadrupole mass spectrometry after positive electrospray ionization by multiple reaction monitoring. The detection and quantitation limits were 1 and 2.5 μg/kg, respectively. The recoveries of edible tissues ranged from 85.3% to 104.9%, with relative standard deviations (RSD) lower than 10.4%. The depletion profile of decoquinate was studied in healthy chickens after oral administration of feed containing 27.2 mg/kg decoquinate for 10 consecutive days. The residue concentrations of decoquinate in chicken muscle and liver were detected using the developed method. The highest residue concentrations were attained 0.25 day post‐treatment, and decoquinate residues were still detected 5 days postmedication in the tissues examined. The developed method has been successfully applied to the depletion study of decoquinate in chicken tissues. The recommended withdrawal period with oral administration based on our research is 3 days.     

Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets

Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment ( t _max = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed ( t _max = 2.25 h) and decreased the rate and extent of absorption ( AUC ) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.     

Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs

OBJECTIVE: To determine the pharmacokinetics of carvedilol administered IV and orally and determine the dose of carvedilol required to maintain plasma concentrations associated with anticipated therapeutic efficacy when administered orally to dogs. ANIMALS: 8 healthy dogs. PROCEDURES: Blood samples were collected for 24 hours after single doses of carvedilol were administered IV (175 microg/kg) or PO (1.5 mg/kg) by use of a crossover nonrandomized design. Carvedilol concentrations were detected in plasma by use of high-performance liquid chromatography. Plasma drug concentration versus time curves were subjected to noncompartmental pharmacokinetic analysis. RESULTS: The median peak concentration (extrapolated) of carvedilol after IV administration was 476 ng/mL (range, 203 to 1,920 ng/mL), elimination half-life (t(1/2)) was 282 minutes (range, 19 to 1,021 minutes), and mean residence time (MRT) was 360 minutes (range, 19 to 819 minutes). Volume of distribution at steady state was 2.0 L/kg (range, 0.7 to 4.3 L/kg). After oral administration of carvedilol, the median peak concentration was 24 microg/mL (range, 9 to 173 microg/mL), time to maximum concentration was 90 minutes (range, 60 to 180 minutes), t(1/2) was 82 minutes (range, 64 to 138 minutes), and MRT was 182 minutes (range, 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range, 0.4% to 54%). CONCLUSIONS AND CLINICAL RELEVANCE: Although results suggested a 3-hour dosing interval on the basis of MRT, pharmacodynamic studies investigating the duration of beta-adrenoreceptor blockade provide a more accurate basis for determining the dosing interval of carvedilol.     

Pharmacokinetics of ketorolac after intravenous and oral single dose administration in dogs

The pharmacokinetics of ketorolac (Toradol), a human non-narcotic, nonsteroidal anti-inflammatory drug (NSAID) of the pyrrolo-pyrrole group, was studied in six mixed breed dogs of varying ages (1-5 years). The study was performed using a randomized crossover design, with each dog initially assigned to one of two groups (intravenous (i.v.) or oral (p.o.)). Each group of three dogs received either the injectable or oral formulation of ketorolac tromethamine at 0.5 mg/kg. Serial blood samples were collected before and over 96 h following treatment. Samples were analysed by reverse phase HPLC. Individual ketorolac plasma concentration-time curves were initially evaluated by computerized curve stripping techniques followed by nonlinear least squares regression. Following i.v. administration mean (+/- SD) pharmacokinetic parameters were: elimination half-life (t1/2 beta) = 4.55 h, plasma clearance (Clp) = 1.25 (1.13) mL/kg/min, and volume of distribution at steady state (Vss) = 0.33 (0.10) L/kg. Mean (+/- SD) p.o. pharmacokinetic values were: t1/2 beta = 4.07 h, time to reach maximum concentration (tmax) = 51.2 (40.6) min, and p.o. bioavailability (F) = 100.9 (46.7)%. These results suggest that the pharmacodisposition characteristics of a clinically effective 0.5 mg/kg i.v. or p.o. single dose of ketorolac tromethamine administered to dogs is fairly similar to that observed in humans.     

Pharmacokinetics and distribution of voriconazole in body fluids of dogs after repeated oral dosing

The goal of this project was to determine the pharmacokinetics of voriconazole and its concentration in cerebrospinal fluid (CSF), aqueous humor, and synovial fluid in five healthy dogs following once daily oral dose of 6 mg?kg for 2 weeks. Body fluid and plasma drug concentrations were determined by high‐performance liquid chromatography (HPLC). Mild to moderate gastrointestinal adverse effects were seen. The mean AUC_0–24: minimum inhibitory concentration (MIC) ratio was 15.23 for a chosen MIC of 1 μg/mL, which is lower than the recommended target of 20–25 and also lower than previously reported in dogs, perhaps reflecting induction of metabolizing enzymes by multiple dosing. Voriconazole concentrations in the CSF, aqueous humor, and synovial fluid were only 13–30% the concurrent plasma concentration, which is lower than previously reported in other species. Results of this study suggest that twice daily, administration may be necessary to maintain therapeutic plasma concentrations in dogs but further studies are warranted.     

Plasma levels of chloramphenicol after oral administration in calves during the first weeks of life

Three experiments were carried out to investigate the mechanisms whereby adequate plasma levels of chloramphenicol may be obtained following oral administration in young calves but not in older animals. In the first experiment, plasma levels of chloramphenicol following an oral dose of 50 mg/kg were followed in six calves, given weekly doses for the first 11 weeks of life. A plasma chloramphenicol level of 5 μg/ml, taken as the minimum therapeutic level, was attained only for a few hours in the 1 week old calves. Thereafter plasma levels decreased very rapidly until the fourth week, and rather more slowly between the fourth and eleventh weeks. At 11 weeks the plasma chloramphenicol level fell to around 0.3 μg/ml, which was the lower limit of sensitivity for the assay technique used. In the second experiment, the same single dose was administered to calves in the twelfth or eighteenth weeks of life which had not previously been exposed to the antibiotic. Plasma levels of 1 μg/ml were barely reached. This suggests that the non-absorbtion of chloramphenicol is unlikely to be related to repeated administration of the antibiotic. In the third experiment, the same single dose was administered orally to two cows. Chloramphenicol could not be detected in the plasma following such administration, and some side-effects were observed in the 48 h following dosing. It is suggested that rumen function may interfere with the absorbtion of chloramphenicol following oral administration to ruminants, even in relatively young animals.