Absorption, distribution, metabolism, and excretion of dirlotapide in the dog

Three once-daily oral doses of 0.2 mg/kg [¹⁴C]dirlotapide were administered to beagle dogs to study the absorption, distribution, metabolism, and excretion of dirlotapide. Mean ¹⁴C recovered at 2.5 and 4.5 h after the last dose was 90%. Mean ¹⁴C in urine, bile, and feces was <1%, 1.7%, and 56% of the dose, respectively. In tissues, 26% of the ¹⁴C dose was present in the gastrointestinal tract, 6.0% in liver, and <1% each in kidney, gall bladder, heart, and brain. To further characterize drug disposition, a single 2.5-mg/kg oral dose of [¹⁴C]dirlotapide was administered to beagle dogs. More than 84% of the dose had been eliminated by 72 h in feces, with 21% of the dose present in feces as parent dirlotapide. Less than 1% of the dose was excreted in urine. In bile collected during the first 24-h postdose from three dogs, 32% and 11% of the ¹⁴C dose was present in samples from male and female dogs, respectively. Based upon metabolite profiling of plasma, excreta, and bile samples, dirlotapide was extensively metabolized to more than 20 metabolites. Biliary/fecal excretion and the potential for enterohepatic recycling of metabolites are suggested.     

Pharmacokinetics of propranolol in the dog

The pharmacokinetics of propranolol were investigated in dogs following intravenous, single oral, and multiple oral doses. Mean half-life of the compound following single intravenous administration was 1.09 h, following single oral dose 1.58 h, and 2.14 h after chronic oral dosing. Half-life values previously reported in dogs for the levo and dextro isomers were 0.77 and 1.08h, respectively. The bioavailability of oral propranolol was low (2–17% available) following a single oral dose, but increased substantially after chronic oral dosing, suggesting saturation of the disposition processes for propranolol with multiple dosing regimens.     

Pharmacokinetics of cefotaxime in the dog

Each of five dogs was given cefotaxime at a dose rate of 50 mg/kg by intravenous, intramuscular and subcutaneous routes, in three separate treatments. Plasma concentration time profiles were characterised by a linear two-compartment model after the intravenous administration. After intravenous, intramuscular and subcutaneous injections the mean biological half-lives were 0.74, 0.83 and 1.71 hours, respectively. The apparent steady state volume of distribution was 0.48 litre/kg and body clearance after intravenous injection was approximately 0.63 litre/hour/kg. After intramuscular and subcutaneous injections peak plasma cefotaxime concentrations were 47 +/- 15 and 29.6 +/- 16 micrograms/ml at 0.5 and 0.8 hours, respectively. The average bioavailability of cefotaxime given by intramuscular injection was 86.5 per cent and for cefotaxime given subcutaneously it was approximately 100 per cent. After two hours, the cefotaxime plasma concentration remained higher after subcutaneous than after intramuscular administration.     

Pharmacokinetics of ticarcillin in the dog

Five healthy adult dogs were given a single IV dose (40 mg/kg of body weight) of ticarcillin disodium. Serum concentrations were measured serially over a period of 12 hours. Five days later, the drug was administered IM to the dogs at the same dose rate, and serum concentrations were measured serially for 12 hours. The mean peak serum concentration after IM administration was 120.5 micrograms/ml at 1.5 hours. Pharmacokinetic values following IV administration were (i) elimination rate constant = 0.8/hour-1, (ii) half-life = 0.8 hour, (iii) serum clearance = 292 ml/hr/kg, and (iv) apparent volume of distribution = 347 ml/kg. Estimated values after IM administration were (i) elimination rate constant = 0.6/hour, (ii) half-life = 1.1 hours, (iii) serum clearance = 218 ml/hr/kg, and (iv) apparent volume of distribution = 345 ml/kg; only the elimination rate constants were significantly different between the 2 routes of administration.     

Pharmacokinetics of oxcarbazepine in the dog

Oxcarbazepine has been proven to be a promising new antiepileptic drug for the treatment of human epilepsy. Unlike carbamazepine, it is not oxidatively metabolized in humans, and therefore causes almost no induction of hepatic enzymes at clinically effective dosages. Though showing similar efficacy to carbamazepine, it has been reported to cause significantly fewer side-effects. It was the purpose of the present study to determine whether oxcarbazepine might be suitable for the treatment of canine epilepsy. In single-dose experiments, 40 mg/kg oxcarbazepine as a suspension was administered to seven dogs via gastric tube. Plasma concentrations reached peak concentrations of 2.4-8.8 μg/mL at about 1.5 h and declined with an elimination half-life of approximately 4 h. The corresponding concentrations of its metabolite, 10.11-dihydro-10-hydroxycarbamazepine, did not exceed 1 μg/mL. During continued treatment for 8 days, doses of 30 and 50 mg/kg were administered orally in capsules to two dogs three times a day. Plasma concentrations showed a pronounced decline from day 3. and the terminal half-life decreased to 2 h and 1 h. This is considered to be the result of oxcarbazepine inducing its own metabolism. The data reveal that oxcarbazepine, compared with former results with carbamazepine, offers no advantage for the treatment of epileptic dogs.     

Pharmacokinetics of lithium in the dog

The pharmacokinetics of lithium were determined in eight adult dogs. The data were fitted to a two-compartment model. Single intravenous doses of lithium chloride, and single oral doses of lithium carbonate were used. The mean plasma lithium half-life (t1/2) following the single intravenous dose was 21.6 h, and the mean apparent specific volume of distribution of the central compartment (V'c) was 0.189 l/kg. Mean bioavailability was 78.8% following oral administration.     

The safety of dirlotapide in dogs

The safety of dirlotapide in dogs was evaluated in two studies with parallel designs. In an acute tolerance study, 24 beagles (six dogs per treatment) were treated orally once daily for 14 days with placebo or dirlotapide at 2.5, 5.0, or 10.0 mg/kg/day. In a margin-of-safety study, 38 overweight, neutered beagles were treated orally once daily for 3 months with dirlotapide at doses up to 0.5 mg/kg/day (six dogs), 1.5 mg/kg/day (12 dogs) and 2.5 mg/kg/day (six dogs). Control dogs received placebo at 0.3 mL/kg/day (10 dogs) and 0.5 mL/kg/day (four dogs). Results were similar for both studies, and no serious adverse events were observed. Dirlotapide was clinically well-tolerated in dogs at dosages up to 10 mg/kg/day for 14 days and 2.5 mg/kg/day for 3 months. Dirlotapide produced the expected decrease in food intake and body weight (up to 20–40%) without ill effects. Clinical, pathologic, and histopathologic findings were reversible and consistent with suppression of food intake and rapid weight loss produced by elevated dirlotapide dosages. In both studies, sporadic emesis and loose stools were observed in both placebo and dirlotapide-treated dogs. Incidence of emesis generally increased with dose and decreased with treatment time. Elevations in hepatic transaminase activity were seen in dogs treated with more than 1.5 mg/kg dirlotapide daily, but were not associated with clinical signs or microscopic evidence of hepatic degeneration or necrosis.     

Pharmacokinetics of three formulations of diphenylhydantoin in the dog

The pharmacokinetics of the sodium salt of diphenylhydantoin was studied in three healthy dogs, using three formulations, a capsule, a tablet and a suspension. The results were essentially the same for all three formulations. The serum half life after intravenous injection ranged from 3.1 to 3.6 hours before and 1.3 to 1.6 hours after a two-week period of oral treatment. The bioavailability of the formulations varied from 43 to 54 per cent. Serum levels likely to be required for canine therapy could not be maintained with any of the formulations used in this experiment.     

Pharmacokinetics and bioavailability of dapsone in the beagle dog

The plasma concentration of dapsone (4,4′-diaminodiphenyl-sulphone) was measured after intravenous and oral administration (±5 mg/kg) to female beagle dogs. Analysis of the plasma concentrations showed a bioavailability of the tablet of 99 per cent. The biological half-life in plasma was estimated to be 13±4 hours after intravenous and 11±5 hours after oral application. In order to test the pharmacokinetic models for their validity a chronic experiment was performed with one dog. The plasma curve, predicted from the oral single-dose data, closely matched the measured experimental data points, which indicates that the applied models are likely to be correct.     

Pharmacokinetics and dosing regimen of aminosidine in the dog

The kinetic behaviour of the aminoglycoside aminosidine, given at 15 mg/kg intravenously, intramuscularly and subcutaneously, was studied in 5 dogs to determine the appropriate dosage schedule. The pharmacokinetic behaviour of aminosidine in dogs was similar to that in other species, except that it was eliminated more slowly (=0.007±0.0003 min^-1). Intramuscular and subcutaneous administration produced peak serum concentrations (C _max[im]=32±6.4 g/ml; C _max[sc]=36±3.4 /ml) and times to peak concentration (T _max=60 min for both) that did not differ significantly; and neither compartmental nor non-compartmental analysis revealed any significant differences between any of the kinetic parameters obtained for these two extravenous routes of administration. Comparison of these results with previously published data suggests that aminosidine given once daily at 15 mg/kg would be as effective as, and safer than, the two or three daily administrations commonly employed in dogs.Abbreviations ALAT alanine aminotransferase - ASAT aspartate aminotransferase - AUC area under the curve - BUN blood urea nitrogen - Cl_b body clearance - C _max peak plasma concentration - CV coefficient of variation - i.m. intramuscular(ly) - i.v. intravenous(ly) - LDH lactate dehydrogenase - MIC minimal inhibitory concentration - MRT mean residence time - PAE post-antibiotic effect - PCV packed cell volume - RBC red blood cell count - s.c. subcutaneous(ly) - SD standard deviation - WBC white blood cell count - V _d(ss) distribution volume at steady state     

Pharmacokinetics of anti-epileptic drugs in the dog: a review

Frey, H.-H. & Löscher, W. Pharmacokinetics of anti-epileptic drugs in the dog: a review. J. vet. Pharmacol. Therap. 8, 219–233.
Dr H.-H. Frey, Laboratory of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, Koserstrasse 20, D-IOOO Berlin 33, West Germany .     

Pharmacokinetics, tolerance and serum thromboxane inhibition of carprofen in the dog

The non-steroidal anti-inflammatory drug (NSAID) carprofen was administered to dogs as a mixed-micelle solution at a dose rate of 0–7 mg/kg intravenously, as a palatable paste at a dose rate of 0–7 mg/kg orally, and as an oral tablet formulation at a dose rate of 0–7 mg/kg and 4-0 mg/kg orally for pharmacokinetic studies. It was also administered as an oral tablet formulation at a dose rate of 9-0 mg/kg orally daily for 14 days in a tolerance study. The pharmacokinetics following intravenous administration at a dose rate of 0–7 mg/kg indicate that carprofen has a small volume of distribution (Vd area = 0–09-0-25 litres), a slow systemic clearance (Cls = 1–34-5-57 ml/min) and an elimination half-life of 3–20-11-77 hours. Both oral paste and tablet preparations were highly bioavailable and absorption was proportional to dose rate at 0–7 mg/kg and 4-0 mg/kg bodyweight. Given once daily at dose rates likely to be used clinically it is unlikely to accumulate in the plasma. Carprofen administered as a palatable paste at a dose rate of 0–7 mg/kg did not inhibit serum thromboxane generation and this drug may therefore have a mode of action different from most NSAIDs. Carprofen was well tolerated when administered as an oral tablet formulation at a dose rate of 9.0 mg/kg daily for 14 days in healthy beagle dogs.     

Pharmacokinetics,pharmacodynamics and therapeutics of pradofloxacin in the dog and cat

Pradofloxacin is a third‐generation fluoroquinolone, licensed in the EU for use in a range of indications in the dog and cat and authorized more recently in the USA for one therapeutic indication (skin infections) in the cat. This review summarizes and appraises current knowledge on the physico‐chemical, pharmacological [pharmacokinetics (PK) and pharmacodynamics (PD)], safety and therapeutic properties of pradofloxacin in the target species. Pradofloxacin contains two centres of asymmetry and is the pure SS enantiomer. After oral dosing of tablets (dog) or tablets and oral suspension (cat), maximum plasma concentrations (C_max) are achieved in less than 3.0 h, and terminal half‐life is of the order of 5–10 h. Accumulation is slight or absent with once daily oral dosing. Free drug concentrations in plasma are in the range of 63–71% of total concentration. As for other fluoroquinolones, antibacterial activity is attributable to inhibition of bacterial replication at two sites, subunit A of topoisomerase II and topoisomerase IV. The antimicrobial spectrum includes gram‐negative and gram‐positive organisms, anaerobes, Mycoplasma spp. and some intracellular organisms (Rickettsia spp. and Mycobacterium spp.). The killing action is of the concentration‐dependent type. Pradofloxacin has high potency (low MIC values) in comparison with first‐ and second‐generation fluoroquinolones. Integration of in vivo PK and in vitro PD data provides values of C_max/MIC and area under plasma concentration–time curve (AUC_24 h)/MIC ratios predictive of good clinical efficacy against sensitive organisms, when administered at recommended dose rates. Clinical trial evaluation of pradofloxacin, in comparison with other authorized antimicrobial drugs, has demonstrated either noninferiority or superiority of pradofloxacin. Data indicating clinical and, in some instances, bacteriological cure have been reported: (i) in cats, for wound infections, abscesses, upper respiratory tract infections, conjunctivitis, feline infectious anaemia and lower urinary tract infections and (ii) in dogs, for wound infections, superficial and deep pyoderma, acute urinary tract infections and adjunctive treatment of infections of gingival and periodontal tissues. At clinical dose rates pradofloxacin was well tolerated in preclinical studies and in clinical trials. Among the advantages of pradofloxacin are (i) successful treatment of infections caused by strains resistant to some other fluoroquinolones, as predicted by PK/PD data, but depending on the specific MIC of the target strain and (ii) a reduced propensity for resistance development based on MPC measurements. The preclinical and clinical data on pradofloxacin suggest that this drug should commonly be the fluoroquinolone of choice when a drug of this class is indicated. However, the PK/PD data on pradofloxacin, in comparison with other fluoroquinolones, are not a factor that leads automatically to greater clinical efficacy.     

Pharmacokinetics of combined intraperitoneal and incisional lidocaine in the dog following ovariohysterectomy

Topical application of local anesthetics provides safe analgesia following abdominal surgery in people. Conservative doses have been utilized to avoid toxicity. Toxic effects are proportional to amount of drug administered and the plasma concentration of the drug, allowing predictions of safety following pharmacokinetic studies. The maximum plasma level, the pharmacokinetics and the safety of lidocaine hydrochloride when administered by the combined intraperitoneal (8 mg/kg i.p. with epinephrine 1:400 000) and incisional (2 mg/kg with epinephrine 1:200 000) routes were studied in six mixed breed dogs following ovariohysterectomy. Rapid uptake of lidocaine produced a peak concentration of 1.45 +/- 0.36 microg/mL (mean +/- SD, range 0.80-1.86 microg/mL) by 0.37 +/- 0.26 h (range 0.11-0.81) after administration. The absorption half-life was 0.13 +/- 0.1 h. Plasma concentrations decreased rapidly and the elimination half-life was 1.17 +/- 0.11 h. No signs of toxicity were observed in these dogs in the 18 h following drug administration. The dose studied generated levels of lidocaine well below toxic.     

Pharmacokinetics and clinical efficacy of a cinchophen and prednisolone combination in the dog

The kinetics and efficacy of a cinchophen prednisolone combination preparation (PLT) were assessed in the dog. Cinchophen administered at a dose rate of 12-5 mg/kg intravenously had a volume of distribution (Vd area) of 0–13 litres/kg, a clearance rate (Cl) of 0–15 litres/h and a half-life (t _1/2β of 7–92 hours. Following oral administration the bioavailability was 87-21 per cent. Prednisolone administered at a dose rate of 0–15 mg/kg intravenously had a Vd area of 2–7 litres/kg, a CI of 0–116 litres/h and a t_1/2β of 1–11 hours. PLT given to dogs with osteoarthritis at a dosage range of between 25 and 44 mg/kg per day cinchophen and between 0–125 and 0–220 mg/kg per day prednisolone for a maximum of 14 days significantly improved lameness (P<0–001), weight bearing (P<0–005), joint mobility (P<0–01) and stiffness (P<0–001) scores and was similar in clinical efficacy to phenylbutazone.     

Evaluation of dirlotapide for sustained weight loss in overweight Labrador retrievers

The effects of dirlotapide on body weight (BW) reduction were investigated in overweight Labradors in two parallel-design studies. Study A involved 42 dogs randomized to 0.0, 0.025, 0.05, 0.1, 0.2 or 0.4 mg dirlotapide/kg/day orally for 4 weeks. Study B involved 72 dogs randomized to nine treatments: placebo (24 weeks); dirlotapide (24 weeks) followed by placebo (28 weeks); or dirlotapide (52 weeks); on diets containing 5%, 10% or 15% fat. Dirlotapide dose (initially 0.1 mg/kg) was adjusted monthly during 24-week weight-loss and subsequent 28-week weight-stabilization phases. Food was offered above maintenance energy requirements (MER× 1.1–1.2) based on initial BW. Body composition (body fat, lean tissue and bone mineral content) was monitored using dual-energy X-ray absorptiometry. After treatment, dogs that had received dirlotapide for 52 weeks were fed 90% of quantity consumed at week 52. In study A, BW and food intake decreased asymptotically with dose: mean weekly weight loss exceeded 1% at 0.1–0.4 mg/kg. In study B, dirlotapide resulted in significant mean weekly weight loss (>0.8%) and decreased food intake over 24 weeks compared with placebo ( P  = 0.0001) for all diets. Food restriction minimized post-treatment weight rebound. Dirlotapide administered daily to dogs for up to 52 weeks was clinically safe and resulted in sustained weight reduction.     

Pharmacokinetics,pharmacodynamics, toxicology and therapeutics of mavacoxib in the dog: a review

Mavacoxib is a novel nonsteroidal anti‐inflammatory drug (NSAID), with a preferential action on the cyclooxygenase (COX)‐2 isoform of COX and a long duration of action. It is classified chemically as a member of the sulphonamide subgroup of coxibs. Mavacoxib is highly lipid but very poorly water soluble. In the dog, the pharmacokinetic (PK) profile comprises very slow body clearance, long elimination half‐life and a relatively large distribution volume. Biotransformation and renal excretion are very limited, and elimination occurs primarily by biliary secretion and excretion of unchanged drug in faeces. The PK profile of mavacoxib differs quantitatively between young healthy dogs (Beagles and mongrels) and clinical cases with osteoarthritis (OA). In OA dogs, mavacoxib exhibits a much longer terminal half‐life, associated principally with their greater median body weight compared with dogs used in preclinical studies. There is also some evidence of breed differences and a small effect of age on mavacoxib PK in the OA canine population. The pharmacodynamics (PD) of mavacoxib has been established: (i) in whole blood assays at the molecular level (inhibition of COX‐1 and COX‐2 isoforms); (ii) in preclinical models of inflammation and pain; and (iii) in clinical OA subjects treated with mavacoxib. The dosage schedule of mavacoxib for clinical use has been determined by owner and veterinary clinical assessments and is supported by integration of PK and PD preclinical data with clinical responses in canine disease models and in dogs with naturally occurring OA. The dosage regimen has been further confirmed by correlating levels of inhibition of COX isoforms in in vitro whole blood assays with plasma concentrations of mavacoxib achieved in OA dogs. In addition to the specific properties of mavacoxib, some general aspects of the PK and PD of other agents of the NSAID group, together with pathophysiological and clinical aspects of OA, are reviewed, as a basis for correlating with the safety and efficacy of mavacoxib in therapeutic use. Integration of PK and PD data suggests that the recommended dosage regimen of 2 mg/kg bw once for 14 days, followed by administration at monthly intervals, is optimal from both efficacy and safety perspectives and is further confirmed by clinical field studies.