Objective—To determine the pharmacokinetics of methylprednisolone (MP) and develop a pharmacokinetic-pharmacodynamic model of the related changes in plasma concentrations of endogenous hydrocortisone (HYD) and cortisone (COR) following intra-articular administration of methylprednisolone acetate (MPA) in horses.
Procedures—In each horse, 200 mg of MPA was injected intrasynovially into a carpal joint, and plasma MP, HYD, and COR concentrations were determined via liquid chromatography-mass spectrometry.
Results—A 5-compartment pharmacokinetic-pharmacodynamic model was used to describe the concatenated changes in the plasma concentrations of MP, HYD, and COR and to estimate the instantaneous rate of endogenous HYD production. The median transfer half-life (t1/2t) of methylprednisolone from the joint to plasma and elimination half-life (t1/2e) from plasma were 1.7 and 19.2 hours, respectively. Maximum plasma concentration of methylprednisolone was 7.26 ± 3.3 ng/mL at 8 hours, which decreased to 0.11 ± 0.08 ng/mL at 144 hours after injection. At 3 hours after MPA administration, plasma COR and HYD concentrations were significantly decreased from baseline values (from 2.9 ± 0.28 ng/mL to 2.10 ± 1.0 ng/mL and from 61.1 ± 18.9 ng/mL to 25.7 ± 12.1 ng/mL, respectively).
Conclusions and Clinical Relevance—The sensitivity of the analytic method used allowed complete description of the related kinetics of MP, HYD, and COR following intra-articular administration of MPA. A single intra-articular administration of MPA profoundly affected the secretion of HYD and COR in horses; secretion of endogenous corticosteroids remained suppressed for as long as 240 hours after injection.
Objective—To evaluate the effect of oral administration of dexamethasone (DEX) at clinically relevant doses on metabolic activities of cytochrome P450 (CYP) isoenzymes in dogs and rats.
Animals—15 healthy 1-year-old male Beagles and 20 healthy 10-week-old male Wistar rats.
Procedure—Hepatic microsomes were harvested from dogs treated orally with DEX at 2.5 and 7.5 mg for 5 days and from rats treated orally with DEX at 0.75, 6, and 48 mg/kg for 5 days. 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam were used as CYP1A, CYP2C, CYP2D, and CYP3A substrates, respectively. Concentrations of metabolites formed by CYPs were measured by use of high-performance liquid chromatography, except for the resorufin concentrations measured by use of a fluorometric method. Reaction velocity-substrate concentration data were analyzed to obtain maximum reaction velocity (Vmax) and Michaelis-Menten constant (Km).
Results—Values of Vmax for midazolam 4-hydroxylation were significantly decreased by treatment with DEX at 2.5 and 7.5 mg in dogs, although values of Km were not affected. Values of Vmax for bufuralol 1'-hydroxylation were also decreased by treatment with DEX. In rats, values of Vmax for midazolam 4- hydroxylation were significantly decreased by treatment with DEX at 0.75 and 6 mg/kg but significantly increased at 48 mg/kg. Other reactions were not affected by treatment with DEX.
Conclusions and Clinical Relevance—Our results indicate that DEX downregulates the CYP3A subfamily when administered at clinically relevant doses to dogs. The effect of downregulation of CYP3A in dogs treated with DEX should be considered to avoid adverse effects from coadministration of drugs.
Procedure—Lidocaine hydrochloride (loading infusion, 1.3 mg/kg during a 15-minute period [87.5 μg/kg/min]; maintenance infusion, 50 μg/kg/min for 60 to 90 minutes) was administered IV to dorsally recumbent anesthetized horses. Blood samples were collected before and at fixed time points during and after lidocaine infusion for analysis of serum drug concentrations by use of liquid chromatography-mass spectrometry. Serum lidocaine concentrations were evaluated by use of standard noncompartmental analysis. Selected cardiopulmonary variables, including heart rate (HR), mean arterial pressure (MAP), arterial pH, PaCO2, and PaO2, were recorded. Recovery quality was assessed and recorded.
Results—Serum lidocaine concentrations paralleled administration, increasing rapidly with the initiation of the loading infusion and decreasing rapidly following discontinuation of the maintenance infusion. Mean ± SD volume of distribution at steady state, total body clearance, and terminal half-life were 0.70 ± 0.39 L/kg, 25 ± 3 mL/kg/min, and 65 ± 33 minutes, respectively. Cardiopulmonary variables were within reference ranges for horses anesthetized with inhalation anesthetics. Mean HR ranged from 36 ± 1 beats/min to 43 ± 9 beats/min, and mean MAP ranged from 74 ± 18 mm Hg to 89 ± 10 mm Hg. Recovery quality ranged from poor to excellent.
Conclusions and Clinical Relevance—Availability of pharmacokinetic data for horses with gastrointestinal tract disease will facilitate appropriate clinical dosing of lidocaine.
Objective—To determine pharmacokinetics, safety, and penetration into interstitial fluid (ISF), polymorphonuclear leukocytes (PMNLs), and aqueous humor of doxycycline after oral administration of single and multiple doses in horses.
Animals—6 adult horses.
Procedure—The effect of feeding on drug absorption was determined. Plasma samples were obtained after administration of single or multiple doses of doxycycline (20 mg/kg) via nasogastric tube. Additionally, ISF, PMNLs, and aqueous humor samples were obtained after the final administration. Horses were monitored for adverse reactions.
Results—Feeding decreased drug absorption. After multiple doses, mean ± SD time to maximum concentration was 1.63 ± 1.36 hours, maximum concentration was 1.74 ± 0.3 μg/mL, and elimination half-life was 12.07 ± 3.17 hours. Plasma protein binding was 81.76 ± 2.43%. The ISF concentrations correlated with the calculated percentage of non-protein-bound drug. Maximum concentration was 17.27 ± 8.98 times as great in PMNLs, compared with plasma. Drug was detected in aqueous humor at 7.5% to 10% of plasma concentrations. One horse developed signs of acute colitis and required euthanasia.
Conclusions and Clinical Relevance—Results suggest that doxycycline administered at a dosage of 20 mg/kg, PO, every 24 hours will result in drug concentrations adequate for killing intracellular bacteria and bacteria with minimum inhibitory concentration ≤ 0.25 μg/mL. For bacteria with minimum inhibitory concentration of 0.5 to 1.0 μg/mL, a dosage of 20 mg/kg, PO, every 12 hours may be required; extreme caution should be exercised with the higher dosage until more safety data are available.
Objective—To evaluate the pharmacokinetics of a novel commercial formulation of ivermectin after administration to goats.
Animals—6 healthy adult goats.
Procedure—Ivermectin (200 μg/kg) was initially administered IV to each goat, and plasma samples were obtained for 36 days. After a washout period of 3 weeks, each goat received a novel commercial formulation of ivermectin (200 μg/kg) by SC injection. Plasma samples were then obtained for 42 days. Drug concentrations were quantified by use of high-performance liquid chromatography with fluorescence detection.
Results—Pharmacokinetics of ivermectin after IV administration were best described by a 2-compartment open model; values for main compartmental variables included volume of distribution at a steady state (9.94 L/kg), clearance (1.54 L/kg/d), and area under the plasma concentration-time curve (AUC; 143 [ng•d]/mL). Values for the noncompartmental variables included mean residence time (7.37 days), AUC (153 [ng•d]/mL), and clearance (1.43 L/kg/d). After SC administration, noncompartmental pharmacokinetic analysis was conducted. Values of the variables calculated by use of this method included maximum plasma concentration (Cmax; 21.8 ng/mL), time to reach Cmax (3 days), and bioavailability (F; 91.8%).
Conclusions and Clinical Relevance—The commercial formulation used in this study is a good option to consider when administering ivermectin to goats because of the high absorption, which is characterized by high values of F. In addition, the values of Cmax and time to reach Cmax are higher than those reported by other investigators who used other routes of administration.
Objective—To determine the effect of dietary n-3 fatty acids on the pharmacokinetics of doxorubicin in dogs with lymphoma.
Animals—23 dogs with lymphoma in stages IIIa, IVa, and Va.
Procedure—Dogs receiving doxorubicin chemotherapy were randomly allocated to receive food with a high (test group) or low (control group) content of n-3 fatty acids. Serum doxorubicin and doxorubicinol concentrations were measured via high-performance liquid chromatography before and 6 to 9 weeks after initiation of the diets. Lymph node concentrations of doxorubicin were assessed 6 hours after the initial treatment. Dogs' body composition was assessed by means of dual-energy x-ray absorptiometry scans.
Results—No significant differences in doxorubicin pharmacokinetics were detected between treatment groups. Significant differences existed between the first and second sampling times among all dogs for area under the curve, maximum serum concentration, and clearance. Differences in body composition did not affect measured pharmacokinetic variables. The terminal elimination half-life was longer in dogs in which a long-term remission was achieved than in dogs that did not have remission.
Conclusions and Clinical Relevance—Dietary supplementation of n-3 fatty acids is common in veterinary patients with neoplasia, but supplementation did not affect doxorubicin pharmacokinetics in this population of dogs. Explanations for the beneficial effects of n-3 fatty acids other than alterations in the pharmacokinetics of chemotherapy drugs should be investigated. Dogs may metabolize drugs differently prior to remission of lymphoma than when in remission. The pharmacokinetics of doxorubicin at the time of the first administration may predict response to treatment.