Objective—To assess pharmacokinetic and pharmacodynamic properties of dexamethasone administered PO as a solution or powder, compared with properties of dexamethasone solution administered IV, in apparently healthy horses.
Animals—6 adult horses.
Procedures—Serum cortisol concentration for each horse was determined before each treatment (baseline values). Dexamethasone (0.05 mg/kg) was administered PO (in solution or powdered form) or IV (solution) to horses from which feed had or had not been withheld (unfed and fed horses, respectively). Each horse received all 6 treatments in random order at 2-week intervals; PO and IV administrations of dexamethasone were accompanied by IV or PO sham treatments, respectively. Plasma dexamethasone and serum cortisol concentrations were assessed at predetermined intervals.
Results—Maximum plasma dexamethasone concentration after PO administration of powdered dexamethasone in unfed horses was significantly higher than the maximum plasma concentration after PO administration of dexamethasone solution in unfed or fed horses. Mean bioavailability of dexamethasone ranged from 28% to 66% but was not significantly different among horses receiving either formulation PO in the unfed or fed state. After dexamethasone treatment PO or IV, serum cortisol concentrations were significantly less than baseline at 1 to 72 hours in unfed horses and at 2 to 48 hours in fed horses.
Conclusions and Clinical Relevance—PO or IV administration of dexamethasone resulted in suppression of cortisol secretion in unfed and fed adult horses; the magnitude of suppression did not differ among treatment groups, and serum cortisol concentrations returned to baseline after 48 to 72 hours.
Procedures—Gabapentin was administered IV (4 mg/kg) or orally (10 mg/kg) in a crossover randomized design. Blood samples were obtained immediately before gabapentin administration and at various times up to 960 minutes after IV administration or up to 1,440 minutes after oral administration. Blood samples were immediately transferred to tubes that contained EDTA and were centrifuged at 4°C. Plasma was harvested and stored at −20°C until analysis. Plasma concentrations of gabapentin were determined by use of liquid chromatography-mass spectrometry. Gabapentin concentration-time data were fit to compartment models.
Results—A 3-compartment model with elimination from the central compartment best described the disposition of gabapentin administered IV to cats, but a 1-compartment model best described the disposition of gabapentin administered orally to cats. After IV administration, the mean ± SEM apparent volume of the central compartment, apparent volume of distribution at steady state, and clearance and the harmonic mean ± jackknife pseudo-SD for terminal half-life were 90.4 ± 11.3 mL/kg, 650 ± 14 mL/kg, 3 ± 0.2 mL/min/kg, and 170 ± 21 minutes, respectively. Mean ± SD systemic availability and harmonic mean ± jackknife pseudo-SD terminal half-life after oral administration were 88.7 ± 11.1% and 177 ± 25 minutes, respectively.
Conclusions and Clinical Relevance—The disposition of gabapentin in cats was characterized by a small volume of distribution and a low clearance.
Objective—To determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis).
Animals—15 clinically normal adult Hispaniolan Amazon parrots.
Procedures—Single doses of voriconazole (12 or 24 mg/kg) were administered orally to 15 and 12 birds, respectively; plasma voriconazole concentrations were determined at intervals via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) or water was administered orally to 6 and 4 birds, respectively, every 8 hours for 11 days (beginning day 0); trough plasma voriconazole concentrations were evaluated on 3 days. Birds were monitored daily, and clinicopathologic variables were evaluated before and after the trial.
Results—Voriconazole elimination half-life was short (0.70 to 1.25 hours). In the single-dose experiments, higher drug doses yielded proportional increases in the maximum plasma voriconazole concentration (Cmax) and area under the curve (AUC). In the multiple-dose trial, Cmax, AUC, and plasma concentrations at 2 and 4 hours were decreased on day 10, compared with day 0 values; however, there was relatively little change in terminal half-life. With the exception of 1 voriconazole-treated parrot that developed polyuria, adverse effects were not evident.
Conclusions and Clinical Relevance—In Hispaniolan Amazon parrots, oral administration of voriconazole was associated with proportional kinetics following administration of single doses and a decrease in plasma concentration following administration of multiple doses. Oral administration of 18 mg of voriconazole/kg every 8 hours would require adjustment to maintain therapeutic concentrations during long-term treatment. Safety and efficacy of voriconazole treatment in this species require further investigation.
Procedures—In experiment 1, 10 market-weight swine were treated with LPS (20 μg/kg, IV [n = 5 swine]) or sham-injected (5) 24 hours before slaughter. In experiment 2, 12 growing and finishing swine were treated with LPS at 2 or 20 μg/kg, IV (n = 3 swine/age group/treatment) 24 hours before slaughter. Hepatic DMEs, cytochrome P450 (CYP) isoforms, and CYP-mediated reactions were measured.
Results—In experiment 1, LPS administered at 20 μg/kg decreased most hepatic DME components and inhibited enzymatic activities. In experiment 2, both doses reduced protein content in subcellular fractions and inhibited some DME- and CYP-mediated activities. In growing and finishing swine, CYP2A and CYP2B isoforms were not detected after treatment with LPS; the CYP1A2 isoform was eliminated in growing but not in finishing swine. Lipopolysaccharide also reduced CYP2D6 content in growing and finishing swine but increased CYP2E content. Lipopolysaccharide had no effect on swine CYP2C11, CYP2C13, or CYP3A content. The CYP2B-mediated 7-pentoxyresorufin O-dealkylase activity in growing and finishing swine was totally eliminated, and 7-ethoxyresorufin (indicating CYP1A activity) and aniline (mediated by CYP2E) metabolism was decreased.
Conclusions and Clinical Relevance—Effect of LPS treatment on swine CYPs appeared to be isoform specific; age-related metabolic status of the swine and the LPS dose modified this effect. Lipopolysaccharide-induced inflammation may affect metabolism of drugs and xenobiotics in swine.
Objective—To determine the stability and distribution of voriconazole in 2 extemporaneously prepared (compounded) suspensions stored for 30 days at 2 temperatures.
Sample Population—Voriconazole suspensions (40 mg/mL) compounded from commercially available 200-mg tablets suspended in 1 of 2 vehicles. One vehicle contained a commercially available suspending agent and a sweetening syrup in a 1:1 mixture (SASS). The other vehicle contained the suspending agent with deionized water in a 3:1 mixture (SADI).
Procedures—Voriconazole suspensions (40 mg/mL in 40-mL volumes) were compounded on day 0 and stored at room temperature (approx 21°C) or refrigerated (approx 5°C). To evaluate distribution, room-temperature aliquots of voriconazole were measured immediately after preparation. Refrigerated aliquots were measured after 3 hours of refrigeration. To evaluate stability, aliquots from each suspension were measured at approximately 7-day intervals for up to 30 days. Voriconazole concentration, color, odor, opacity, and pH were measured, and aerobic and anaerobic bacterial cultures were performed at various points.
Results—Drug distribution was uniform (coefficient of variation, < 5%) in both suspensions. On day 0, 87.8% to 93.0% of voriconazole was recovered; percentage recovery increased to between 95.1% and 100.8% by day 7. On subsequent days, up to day 30, percentage recovery was stable (> 90%) for all suspensions. The pH of each suspension did not differ significantly throughout the 30-day period. Storage temperature did not affect drug concentrations at any time, nor was bacterial growth obtained.
Conclusions and Clinical Relevance—Extemporaneously prepared voriconazole in SASS and SADI resulted in suspensions that remained stable for at least 30 days. Refrigerated versus room-temperature storage of the suspensions had no effect on drug stability.
Objective—To investigate cytochrome P450 (CYP) enzymes involved in metabolism of racemic and S-ketamine in various species and to evaluate metabolic interactions of other analgesics with ketamine.
Sample Population—Human, equine, and canine liver microsomes.
Procedures—An analgesic was concurrently incubated with luminogenic substrates specific for CYP 3A4 or CYP 2C9 and liver microsomes. The luminescence signal was detected and compared with the signal for negative control samples. Ketamine and norketamine enantiomers were determined by use of capillary electrophoresis.
Results—A concentration-dependent decrease in luminescence signal was detected for ibuprofen and diclofenac in the assay for CYP 2C9 in human and equine liver microsomes but not in the assay for CYP 3A4 and methadone or xylazine in any of the species. Coincubation of methadone or xylazine with ketamine resulted in a decrease in norketamine formation in equine and canine liver microsomes but not in human liver microsomes. In all species, norketamine formation was not affected by ibuprofen, but diclofenac reduced norketamine formation in human liver microsomes. A higher rate of metabolism was detected for S-ketamine in equine liver microsomes, compared with the rate for the S-enantiomer in the racemic mixture when incubated with any of the analgesics investigated.
Conclusions and Clinical Relevance—Enzymes of the CYP 3A4 family and orthologs of CYP 2C9 were involved in ketamine metabolism in horses, dogs, and humans. Methadone and xylazine inhibited in vitro metabolism of ketamine. Therefore, higher concentrations and diminished clearance of ketamine may cause adverse effects when administered concurrently with other analgesics.
Objective—To determine pharmacokinetics and oral bioavailability of metformin in healthy horses.
Animals—4 adult horses.
Procedures—6 g of metformin was administered 3 times IV and PO (fed and unfed) to each horse, by use of a crossover design, with a 1-week washout period between treatments. Plasma metformin concentration was determined via high-pressure liquid chromatography.
Results—Mean ± SD distribution half-life of metformin following IV administration was 24.9 ± 0.4 minutes with a volume of distribution of 0.3 ± 0.1 L/kg. Mean area under the curve was 20.9 ± 2.0 h·μg/mL for IV administration; PO administration resulted in area under the curves of 1.6 ± 0.4 h·μg/mL in unfed horses and 0.8 ± 0.2 h·μg/mL in fed horses. Bioavailability was determined to be approximately 7.1 ± 1.5% in unfed horses and 3.9 ± 1.0% in fed horses. The maximal concentration following PO administration in unfed horses was 0.4 ± 0.1 μg/mL with a time at maximal concentration of 0.9 ± 0.1 hours. In fed horses, maximal concentration was reduced to 0.3 ± 0.04 μg/mL with a time at maximal concentration at 1.3 ± 0.3 hours.
Conclusions and Clinical Relevance—The low bioavailability of metformin may explain the reported lack of clinical success in improving insulin sensitivity with metformin treatment in horses. Dosages and dose intervals previously used may have been insufficient to achieve plasma concentrations of drug comparable to the therapeutic range achieved in humans. Therefore, a larger and more frequently administered dose may be required to fully evaluate efficacy of metformin in horses.
Objective—To determine the pharmacokinetics of marbofloxacin after oral administration every 24 hours to rabbits during a 10-day period.
Animals—8 healthy 9-month-old female New Zealand White rabbits.
Procedures—Marbofloxacin (5 mg/kg) was administered orally every 24 hours to 8 rabbits for 10 days. The first day of administration was designated as day 1. Blood samples were obtained at 0, 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours on days 1 and 10 of marbofloxacin administration. Plasma marbofloxacin concentrations were quantitated by use of a validated liquid chromatography–mass spectrometry assay. Pharmacokinetic analysis of marbofloxacin was analyzed via noncompartmental methods.
Results—After oral administration, mean ± SD area under the curve was 10.50 ± 2.00 μg·h/mL and 10.90 ± 2.45 μg·h/mL, maximum plasma concentration was 1.73 ± 0.35 μg/mL and 2.56 ± 0.71 μg/mL, and harmonic mean terminal half-life was 8.0 hours and 3.9 hours for days 0 and 10, respectively.
Conclusions and Clinical Relevance—Marbofloxacin administered orally every 24 hours for 10 days appeared to be absorbed well and tolerated by rabbits. Administration of marbofloxacin at a dosage of 5 mg/kg, PO, every 24 hours is recommended for rabbits to control infections attributable to susceptible bacteria.
Objective—To compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation β1-adrenoceptor–selective blocking agent, with those of carvedilol, a third-generation β1/β2 and α1-adrenoceptor blocking agent, in dogs.
Animals—12 healthy adult Beagles.
Procedures—A prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed.
Results—After oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 μg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 μg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 μg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 μg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol.
Conclusions and Clinical Relevance—After oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.
Objective—To determine the pharmacokinetics after SC administration of an experimental, long-acting parenteral formulation of doxycycline hyclate in a poloxamer-based matrix and after IV and IM administration of an aqueous formulation of doxycycline hyclate in goats.
Animals—30 clinically normal adult goats.
Procedures—Goats were allocated to 3 groups (10 goats/group). One group of goats received doxycycline hyclate (10 mg/kg) IM, a second group received the same dosage of doxycycline hyclate IV, and the third group received the long-acting parenteral formulation of doxycycline hyclate SC. Serum concentrations of doxycycline were determined before and at various intervals after administration.
Results—The long-acting parenteral formulation of doxycycline hyclate had the greatest bioavailability (545%); mean ± SD maximum serum concentration was 2.4 ± 0.95 μg/mL, peak time to maximum concentration was 19.23 ± 2.03 hours, and elimination half-life was 40.92 ± 4.25 hours.
Conclusions and Clinical Relevance—Results indicated that the long-acting parenteral formulation of doxycycline hyclate distributed quickly and widely throughout the body after a single dose administered SC, and there was a prolonged half-life. Bioavailability of the longacting parenteral formulation of doxycycline hyclate after SC administration was excellent, compared with bioavailability after IV and IM administration of an aqueous formulation of doxycycline hyclate. Although no local tissue irritation and adverse effects were detected, clinical assessment of drug-residues and toxicologic evaluations are warranted before this long-acting parenteral formulation of doxycycline hyclate can be considered for use in goats with bacterial infections.