OBJECTIVE To assess the possible impact of medetomidine on concentrations of alfaxalone in plasma, when coadministered as a constant rate infusion (CRI) to dogs, and to determine the possible impact of medetomidine on the cardiopulmonary effects of alfaxalone during CRI.
ANIMALS 8 healthy adult Beagles.
PROCEDURES 3 treatments were administered in a randomized crossover design as follows: 1 = saline (0.9% NaCl) solution injection, followed in 10 minutes by induction of anesthesia with alfaxalone (loading dose, 2.4 mg/kg; CRI, 3.6 mg/kg/h, for 60 minutes); 2 = medetomidine premedication (loading dose, 4.0 μg/kg; CRI, 4.0 μg/kg/h), followed by alfaxalone (as in treatment 1); and, 3 = medetomidine (as in treatment 2) and MK-467 (loading dose, 150 μg/kg; CRI, 120 μg/kg/h), followed by alfaxalone (as in treatment 1). The peripherally acting α2-adrenoceptor antagonist MK-467 was used to distinguish between the peripheral and central effects of medetomidine. Drugs were administered IV via cephalic catheters, and there was a minimum of 14 days between treatments. Cardiopulmonary parameters were measured for 70 minutes, and jugular venous blood samples were collected until 130 minutes after premedication. Drug concentrations in plasma were analyzed with liquid chromatography–tandem mass spectrometry.
RESULTS The characteristic cardiovascular effects of medetomidine, such as bradycardia, hypertension, and reduction in cardiac index, were obtunded by MK-467. The concentrations of alfaxalone in plasma were significantly increased in the presence of medetomidine, indicative of impaired drug distribution and clearance. This was counteracted by MK-467.
CONCLUSIONS AND CLINICAL RELEVANCE The alteration in alfaxalone clearance when coadministered with medetomidine may be attributed to the systemic vasoconstrictive and bradycardic effects of the α2-adrenoceptor agonist. This could be clinically important because the use of α2-adrenoceptor agonists may increase the risk of adverse effects if standard doses of alfaxalone are used.
OBJECTIVE To determine the pharmacokinetics of meloxicam in domestic hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg).
ANIMALS 8 healthy adult White Leghorn hens.
PROCEDURES Hens were administered 1 mg of meloxicam/kg PO once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma, egg whites (albumen), and egg yolks were analyzed by high-performance liquid chromatography.
RESULTS The half-life, maximum concentration, and time to maximum concentration of meloxicam in plasma samples were 2.8 hours, 7.21 μg/mL, and 2 hours, respectively. Following meloxicam administration, the drug was not detected after 4 days in egg whites and after 8 days in egg yolks.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that meloxicam administered at a dose of 1 mg/kg PO in chickens appears to maintain plasma concentrations equivalent to those reported to be therapeutic for humans for 12 hours. The egg residue data may be used to aid establishment of appropriate drug withdrawal time recommendations.
OBJECTIVE To determine pharmacokinetics and pharmacodynamics of buprenorphine after IV and SC administration and of sustained-release (SR) buprenorphine after SC administration to adult alpacas.
ANIMALS 6 alpacas.
PROCEDURES Buprenorphine (0.02 mg/kg, IV and SC) and SR buprenorphine (0.12 mg/kg, SC) were administered to each alpaca, with a 14-day washout period between administrations. Twenty-one venous blood samples were collected over 96 hours and used to determine plasma concentrations of buprenorphine. Pharmacokinetic parameters were calculated by use of noncompartmental analysis. Pharmacodynamic parameters were assessed via sedation, heart and respiratory rates, and thermal and mechanical antinociception indices.
RESULTS Mean ± SD maximum concentration after IV and SC administration of buprenorphine were 11.60 ± 4.50 ng/mL and 1.95 ± 0.80 ng/mL, respectively. Mean clearance was 3.00 ± 0.33 L/h/kg, and steady-state volume of distribution after IV administration was 3.8 ± l.0 L/kg. Terminal elimination half-life was 1.0 ± 0.2 hours and 2.7 ± 2.8 hours after IV and SC administration, respectively. Mean residence time was 1.3 ± 0.3 hours and 3.6 ± 3.7 hours after IV and SC administration, respectively. Bioavailability was 64 ± 28%. Plasma concentrations after SC administration of SR buprenorphine were below the LLOQ in samples from 4 alpacas. There were no significant changes in pharmacodynamic parameters after buprenorphine administration. Alpacas exhibited mild behavioral changes after all treatments.
CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine administration to healthy alpacas resulted in moderate bioavailability, rapid clearance, and a short half-life. Plasma concentrations were detectable in only 2 alpacas after SC administration of SR buprenorphine.
To determine the pharmacokinetics of terbinafine in little brown myotis (Myotis lucifugus) infected with Pseudogymnoascus destructans.
123 bats from a P destructans–infected hibernation site in Virginia.
3 bats were euthanized and necropsied to confirm the presence of P destructans within the population. The remaining 120 bats were systematically assigned to 6 groups (20 bats/group). Bats in each of 3 groups received 6, 20, or 60 mg of terbinafine/kg, SC, once daily for 10 days. Bats in another group received 200 mg of terbinafine/kg, SC, once daily for 5 days. Bats in 1 group received the terbinafine vehicle solution (0.1 mL/kg, SC, once daily for 10 days). Bats in the remaining group did not receive any treatment. Following the treatment period (days 1 through 10), bats were housed in a hibernation chamber and monitored daily until euthanasia on day 42, 75, or 109. Tissue specimens were collected from all bats as soon as possible after death or euthanasia to determine terbinafine concentration. Within each group and tissue type, terbinafine concentration data were pooled, and pharmacokinetic parameters were calculated by noncompartmental methods.
Adverse neurologic effects and a high mortality rate before day 10 were observed in bats that received the highest terbinafine dose (200 mg/kg) but not those that received lower doses. Presumed therapeutic terbinafine concentrations (≥ 2 μg/g) were maintained in skin and wing for at least 30 and 6 days in bats that received the 60 and 20 mg/kg doses, respectively, but were not achieved in most bats that received the 6 mg/kg dose. Tissue terminal half-life ranged from 14 to 22 days. Terbinafine concentration in hair was positively correlated with that in skin and wing.
CONCLUSIONS AND CLINICAL RELEVANCE
Results indicated terbinafine doses > 6 but < 200 mg/kg should be further evaluated for the treatment of P destructans–infected bats. Collection of serial hair specimens may represent a noninvasive method for monitoring terbinafine concentration in treated bats.
OBJECTIVE To determine pharmacodynamic and pharmacokinetic profiles of aminocaproic acid (ACA) by use of a thromboelastography (TEG)-based in vitro model of hyperfibrinolysis and high-performance liquid chromatography–mass spectrometry.
ANIMALS 5 healthy adult dogs.
PROCEDURES A single dose of injectable ACA (20, 50, or 100 mg/kg) or an ACA tablet (approximately 100 mg/kg) was administered orally. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, and 240 minutes after ACA administration for pharmacokinetic analysis. Samples were obtained at 0, 60, and 240 minutes for pharmacodynamic analysis by use of a TEG model of hyperfibrinolysis.
RESULTS No adverse effects were detected. In the hyperfibrinolysis model, after all doses, a significantly higher TEG maximum amplitude (clot strength), compared with baseline, was detected at 60 and 240 minutes. Additionally, the percentage of fibrinolysis was reduced from the baseline value at 60 and 240 minutes, with the greatest reduction at 60 minutes. At 240 minutes, there was significantly less fibrinolysis for the 100 mg/kg dose than the 20 mg/kg dose. Maximum plasma ACA concentration was dose dependent. There was no significant difference in pharmacokinetic parameters between 100 mg/kg formulations.
CONCLUSIONS AND CLINICAL RELEVANCE In an in vitro model of hyperfibrinolysis, ACA inhibited fibrinolysis at all doses tested. At 240 minutes after administration, the 100 mg/kg dose inhibited fibrinolysis more effectively than did the 20 mg/kg dose. Thus, ACA may be useful for in vivo prevention of fibrinolysis in dogs.
IMPACT FOR HUMAN MEDICINE These data may improve research models of hyperfibrinolytic diseases.
OBJECTIVE To determine population pharmacokinetics of enrofloxacin in purple sea stars (Pisaster ochraceus) administered an intracoelomic injection of enrofloxacin (5 mg/kg) or immersed in an enrofloxacin solution (5 mg/L) for 6 hours.
ANIMALS 28 sea stars of undetermined age and sex.
PROCEDURES The study had 2 phases. Twelve sea stars received an intracoelomic injection of enrofloxacin (5 mg/kg) or were immersed in an enrofloxacin solution (5 mg/L) for 6 hours during the injection and immersion phases, respectively. Two untreated sea stars were housed with the treated animals following enrofloxacin administration during both phases. Water vascular system fluid samples were collected from 4 sea stars and all controls at predetermined times during and after enrofloxacin administration. The enrofloxacin concentration in those samples was determined by high-performance liquid chromatography. For each phase, noncompartmental analysis of naïve averaged pooled samples was used to obtain initial parameter estimates; then, population pharmacokinetic analysis was performed that accounted for the sparse sampling technique used.
RESULTS Injection phase data were best fit with a 2-compartment model; elimination half-life, peak concentration, area under the curve, and volume of distribution were 42.8 hours, 18.9 μg/mL, 353.8 μg•h/mL, and 0.25 L/kg, respectively. Immersion phase data were best fit with a 1-compartment model; elimination half-life, peak concentration, and area under the curve were 56 hours, 36.3 μg•h/mL, and 0.39 μg/mL, respectively.
CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the described enrofloxacin administration resulted in water vascular system fluid drug concentrations expected to exceed the minimum inhibitory concentration for many bacterial pathogens.
OBJECTIVE To characterize polymorphisms of the gene for cytochrome P450 isozyme 2D50 (CYP2D50) and the disposition of 2 CYP2D50 probe drugs, dextromethorphan and debrisoquine, in horses.
ANIMALS 23 healthy horses (22 Thoroughbreds and 1 Standardbred).
PROCEDURES Single-nucleotide polymorphisms (SNPs) in CYP2D50 were identified. Disposition of dextromethorphan (2 mg/kg) and debrisoquine (0.2 mg/kg) were determined after oral (dextromethorphan) or nasogastric (debrisoquine) administration to the horses. Metabolic ratios of plasma dextromethorphan and total dextrorphan (dextrorphan plus dextrorphan-O-β-glucuronide) and 4-hydroxydebrisoquine concentrations were calculated on the basis of the area under the plasma concentration-versus-time curve extrapolated to infinity for the parent drug divided by that for the corresponding metabolite. Pharmacokinetic data were used to categorize horses into the phenotypic drug-metabolism categories poor, extensive, and ultrarapid. Disposition patterns were compared among categories, and relationships between SNPs and metabolism categories were explored.
RESULTS Gene sequencing identified 51 SNPs, including 27 nonsynonymous SNPs. Debrisoquine was minimally detected after oral administration. Disposition of dextromethorphan varied markedly among horses. Metabolic ratios for dextromethorphan ranged from 0.03 to 0.46 (mean, 0.12). On the basis of these data, 1 horse was characterized as a poor metabolizer, 18 were characterized as extensive metabolizers, and 3 were characterized as ultrarapid metabolizers.
CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that CYP2D50 is polymorphic and that the disposition of the probe drug varies markedly in horses. The polymorphisms may be related to rates of drug metabolism. Additional research involving more horses of various breeds is needed to fully explore the functional implication of polymorphisms in CYP2D50.
OBJECTIVE To evaluate pharmacokinetics and bioavailability after administration of ceftiofur hydrochloride and ceftiofur sodium to water buffalo (Bubalus bubalis).
ANIMALS 5 healthy adult water buffalo (3 males and 2 nonlactating females).
PROCEDURES All animals received a dose (2.2 mg/kg) of 3 ceftiofur products (2 commercially available suspensions of ceftiofur hydrochloride [CEF1 and CEF2, IM] and ceftiofur sodium [CEF3, IV]). Blood samples were collected for up to 196 hours. Concentrations of ceftiofur in plasma were determined by use of high-performance liquid chromatography, and pharmacokinetic parameters were calculated on the basis of noncompartmental methods.
RESULTS Most of the pharmacokinetic parameters, except for bioavailability and the area under the concentration–time curve extrapolated to infinity, were significantly different between the 2 products administered IM. Mean ± SD bioavailability of CEF1 and CEF2 was 89.57 ± 32.84% and 86.28 ± 11.49%, respectively, which indicated good absorption of both products. In addition, there was a longer drug residence time for CEF1 than for CEF2. Data analysis for CEF1 revealed a flip-flop phenomenon.
CONCLUSIONS AND CLINICAL RELEVANCE In this study, there was good absorption of CEF1, and CEF1 had a longer drug residence time in vivo than did CEF2. On the basis of pharmacokinetic parameters and the in vitro antimicrobial susceptibility, a dosage regimen of 2.2 mg/kg administered at 48- and 36-hour intervals for CEF1 and CEF2, respectively, could be an appropriate choice for the treatment of buffalo with infectious diseases.
OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves.
ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old.
PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after the first and last doses. Beginning 24 hours after injection of the last dose, 4 calves were euthanized each day for 5 days. Plasma and tissue samples were analyzed by ultraperformance liquid chromatography. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods.
RESULTS Mean ± SD plasma flunixin elimination half-life, residence time, and clearance were 1.32 ± 0.94 hours, 12.54 ± 10.96 hours, and 64.6 ± 40.7 mL/h/kg, respectively. Mean hepatic and muscle flunixin concentrations decreased to below FDA-established tolerance limits (0.125 and 0.025 μg/mL, respectively) for adult cattle by 3 and 2 days, respectively, after injection of the last dose of flunixin. Detectable flunixin concentrations were present in both the liver and muscle for at least 5 days after injection of the last dose.
CONCLUSIONS AND CLINICAL RELEVANCE The labeled slaughter withdrawal interval for flunixin in adult cattle is 4 days. Because administration of flunixin to veal calves represents extralabel drug use, any detectable flunixin concentrations in edible tissues are considered a violation. Results indicated that a slaughter withdrawal interval of several weeks may be necessary to ensure that violative tissue residues of flunixin are not detected in veal calves treated with that drug.
OBJECTIVE To evaluate pharmacokinetics of bupivacaine after IP administration to cats undergoing ovariohysterectomy.
ANIMALS 8 healthy cats.
PROCEDURES Anesthesia was induced with propofol and maintained with isoflurane. Buprenorphine (0.02 mg/kg, IV) and meloxicam (0.2 mg/kg, SC) were administered. A 20-gauge catheter was inserted into a jugular vein for blood sample collection. A ventral midline incision was made, and a solution of 0.5% bupivacaine (2 mg/kg) diluted with an equal volume of saline (0.9% NaCl) solution (final concentration, 0.25% bupivacaine) was injected into the peritoneal space over the right and left ovarian pedicles and caudal aspect of the uterus before ovariohysterectomy. Cats were monitored for signs of bupivacaine toxicosis. Venous blood samples (2 mL) were collected before (time 0) and 2, 5, 10, 15, 20, 30, 60, 120, and 240 minutes after bupivacaine administration. Plasma bupivacaine concentrations were determined with a liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were determined by data plotting followed by analysis with a noncompartmental model.
RESULTS No signs of bupivacaine toxicosis were observed. Maximum bupivacaine plasma concentration was 1,030 ± 497.5 ng/mL at a mean ± SD value of 30 ± 24 minutes after administration. Mean elimination half-life was 4.79 ± 2.7 hours. Mean clearance indexed by bioavailability and volume of distribution indexed by bioavailability were 0.35 ± 0.18 L•h/kg and 2.10 ± 0.84 L/kg, respectively.
CONCLUSIONS AND CLINICAL RELEVANCE Intraperitoneal administration of bupivacaine resulted in concentrations that did not cause observable toxicosis. Studies to investigate analgesic effects for this technique in cats are warranted.