Objective—To identify a subantimicrobial dose of doxycycline hyclate (SDD) and for the treatment of periodontitis in dogs.
Animals—20 healthy Beagles for measurement of serum doxycycline concentration and 15 Beagles with periodontitis for evaluation of the efficacy of the SDD.
Procedures—5 dogs each received doxycycline hyclate PO at a dose of 1, 2, 3, or 5 mg/kg. Blood samples were collected before and after administration, and serum concentrations of doxycycline were measured via high-performance liquid chromatography. Mean serum doxycycline concentrations were calculated, and SDDs were identified. In a separate trial, the identified SDDs (1 or 2 mg/kg) were administered PO once a day for 1 month to dogs with periodontitis (n = 5/group) and a control group (5) was fed vehicle only during the same period. Degree of gingival attachment and bleeding on probing (present or absent) were recorded. Gingival samples were collected before and after the 1-month period from the same anatomic sites. Degree of matrix metalloproteinase inhibition in gingival samples was determined via gelatin zymography and compared among treatment groups.
Results—Mean serum doxycycline concentrations in healthy dogs that received 1 or 2 mg of doxycycline/kg were consistently significantly lower than the minimal inhibitory doxycycline concentration for treatment of periodontitis throughout the 24-hour posttreatment period. Zymographic intensities were lower in dogs given 1 and 2 mg/kg than in the control dogs, and the degree of gingival attachment and bleeding significantly improved in dogs given 2 mg/kg, compared with in the control dogs and dogs given 1 mg of doxycycline/kg.
Conclusions and Clinical Relevance—A doxycycline dosage of 2 mg/kg daily appeared to be an appropriate subantimicrobial regimen for dogs with periodontitis. Furthermore, this dosage may be suitable for long-term treatment of gelatinolytic inflammatory diseases such as periodontitis in this species.
Objective—To determine plasma pharmacokinetics of penciclovir following oral and rectal administration of famciclovir to young Asian elephants (Elephas maximus).
Animals—6 healthy Asian elephants (5 females and 1 male), 4.5 to 9 years old and weighing 1,646 to 2,438 kg.
Procedures—Famciclovir was administered orally or rectally in accordance with an incomplete crossover design. Three treatment groups, each comprising 4 elephants, received single doses of famciclovir (5 mg/kg, PO, or 5 or 15 mg/kg, rectally); there was a minimum 12-week washout period between subsequent famciclovir administrations. Serial blood samples were collected after each administration. Samples were analyzed for famciclovir and penciclovir with a validated liquid chromatography–mass spectroscopy assay.
Results—Famciclovir was tolerated well for both routes of administration and underwent complete biotransformation to the active metabolite, penciclovir. Mean maximum plasma concentration of penciclovir was 1.3 μg/mL at 1.1 hours after oral administration of 5 mg/kg. Similar results were detected after rectal administration of 5 mg/kg. Mean maximum plasma concentration was 3.6 μg/mL at 0.66 hours after rectal administration of 15 mg/kg; this concentration was similar to results reported for humans receiving 7 mg/kg orally.
Conclusions and Clinical Relevance—Juvenile Asian elephants are susceptible to elephant endotheliotropic herpesvirus. Although most infections are fatal, case reports indicate administration of famciclovir has been associated with survival of 3 elephants. In Asian elephants, a dose of 8 to 15 mg of famciclovir/kg given orally or rectally at least every 8 hours may result in penciclovir concentrations that are considered therapeutic in humans.
Objective—To model the plasma tetracycline concentrations in swine (Sus scrofa domestica) treated with medication administered in water and determine the factors that contribute to the most accurate predictions of measured plasma drug concentrations.
Sample—Plasma tetracycline concentrations measured in blood samples from 3 populations of swine.
Procedures—Data from previous studies provided plasma tetracycline concentrations that were measured in blood samples collected from 1 swine population at 0, 4, 8, 12, 24, 32, 48, 56, 72, 80, 96, and 104 hours and from 2 swine populations at 0, 12, 24, 48, and 72 hours hours during administration of tetracycline hydrochloride dissolved in water. A 1-compartment pharmacostatistical model was used to analyze 5 potential covariate schemes and determine factors most important in predicting the plasma concentrations of tetracycline in swine.
Results—2 models most accurately predicted the tetracycline plasma concentrations in the 3 populations of swine. Factors of importance were body weight or age of pig, ambient temperature, concentration of tetracycline in water, and water use per unit of time.
Conclusions and Clinical Relevance—The factors found to be of importance, combined with knowledge of the individual pharmacokinetic and chemical properties of medications currently approved for administration in water, may be useful in more prudent administration of approved medications administered to swine. Factors found to be important in pharmacostatistical models may allow prediction of plasma concentrations of tetracycline or other commonly used medications administered in water. The ability to predict in vivo concentrations of medication in a population of food animals can be combined with bacterial minimum inhibitory concentrations to decrease the risk of developing antimicrobial resistance.
Objective—To evaluate the pharmacokinetics and pharmacodynamics of zolpidem after oral administration of a single dose (0.15 or 0.50 mg/kg) and assess any associated antianxiety and sedative effects in dogs.
Animals—8 clinically normal sexually intact male dogs of various breeds.
Procedures—Dogs were assigned to 2 groups (4 dogs/group) and administered zolpidem orally once at a dose of 0.15 or 0.50 mg/kg in a crossover study; each dog received the other treatment once after an interval of 1 week. Blood samples were collected before and at intervals during the 24-hour period following dose administration. For each time point, plasma zolpidem concentration was evaluated via a validated method of high-performance liquid chromatography coupled with fluorescence detection, and pharmacodynamics were assessed via subjective assessments of sedation and level of agitation and selected clinical variables.
Results—The pharmacokinetic profile of zolpidem in dogs was dose dependent, and the plasma drug concentrations attained were lower than those for humans administered equivalent doses. The lower dose did not result in any clinical or adverse effects, but the higher dose generated paradoxical CNS stimulation of approximately 1 hour's duration and a subsequent short phase of mild sedation. This sedation phase was not considered to be of clinical relevance. The desired clinical effects were not evident at plasma zolpidem concentrations ≤ 30 ng/mL, and the minimal plasma concentration that induced adverse effects was 60 ng/mL.
Conclusions and Clinical Relevance—Results indicated that zolpidem is not a suitable drug for inducing sedation in dogs.
Objective—To determine the tissue depletion profile of tulathromycin and determine an appropriate slaughter withdrawal interval in meat goats after multiple SC injections of the drug.
Animals—16 healthy Boer goats.
Procedures—All goats were administered tulathromycin (2.5 mg/kg, SC) twice, with a 7-day interval between doses. Blood samples were collected throughout the study, and goats were euthanized at 2, 5, 10, and 20 days after the second tulathromycin dose. Lung, liver, kidney, fat, and muscle tissues were collected. Concentrations of tulathromycin in plasma and the hydrolytic tulathromycin fragment CP-60,300 in tissue samples were determined with ultrahigh-pressure liquid chromatography–tandem mass spectrometry.
Results—The plasma profile of tulathromycin was biphasic. Absorption was very rapid, with maximum drug concentrations (1.00 ± 0.42 μg/mL and 2.09 ± 1.77 μg/mL following the first and second doses, respectively) detected within approximately 1 hour after injection. Plasma terminal elimination half-life of tulathromycin was 61.4 ± 14.1 hours after the second dose. Half-lives in tissue ranged from 2.4 days for muscle to 9.0 days for lung tissue; kidney tissue was used to determine the withdrawal interval for tulathromycin in goats because it is considered an edible tissue.
Conclusions and Clinical Relevance—On the basis of the tissue tolerance limit in cattle of 5 ppm (μg/g), the calculated withdrawal interval for tulathromycin would be 19 days following SC administration in goats. On the basis of the more stringent guidelines recommended by the FDA, the calculated meat withdrawal interval following tulathromycin administration in goats was 34 days.
Objective—To determine the pharmacokinetics of methylprednisolone (MP) and the relationship between MP and hydrocortisone (HYD) concentrations in plasma and urine after intra-articular (IA) administration of 100 or 200 mg of MP acetate (MPA) to horses.
Animals—Five 3-year-old Thoroughbred mares.
Procedures—Horses exercised on a treadmill 3 times/wk during the study. Horses received 100 mg of MPA IA, then 8 weeks later received 200 mg of MPA IA. Plasma and urine samples were obtained at various times for 8 weeks after horses received each dose of MPA; concentrations of MP and HYD were determined. Pharmacokinetic-pharmacodynamic estimates for noncompartmental and compartmental parameters were determined.
Results—Maximum concentration of MP in plasma was similar for each MPA dose; concentrations remained greater than the lower limit of quantitation for 18 and 7 days after IA administration of 200 and 100 mg of MPA, respectively. Maximum concentration and area under the observed concentration-time curve for MP in urine were significantly higher (approximately 10-and 17-fold, respectively) after administration of 200 versus 100 mg of MPA. Hydrocortisone concentration was below quantifiable limits for ≥ 48 hours in plasma and urine of all horses after administration of each MPA dose.
Conclusions and Clinical Relevance—Pharmacokinetics of MP may differ among IA MPA dosing protocols, and MP may be detected in plasma and urine for a longer time than previously reported. This information may aid veterinarians treating sport horses. Further research is warranted to determine whether plasma HYD concentration can aid identification of horses that received exogenous glucocorticoids.
Objective—To determine the pharmacokinetics of ciprofloxacin in dogs, including oral absorption following administration of generic ciprofloxacin tablets.
Animals—6 healthy Beagles.
Procedures—In a crossover study design, ciprofloxacin was administered as a generic tablet (250 mg, PO; mean dose, 23 mg/kg) and solution (10 mg/kg, IV) to 6 dogs. In a separate experiment, 4 of the dogs received ciprofloxacin solution (10 mg/mL) PO via stomach tube (total dose, 250 mg). Blood samples were collected before (time 0) and for 24 hours after each dose. Plasma concentrations were analyzed with high-pressure liquid chromatography. Pharmacokinetic analysis was performed by means of compartmental modeling.
Results—When ciprofloxacin was administered as tablets PO, peak plasma concentration was 4.4 μg/mL (coefficient of variation [CV], 55.9%), terminal half-life (t1/2) was 2.6 hours (CV, 10.8%), area under the time-concentration curve was 22.5 μg•h/mL (CV, 62.3%), and systemic absorption was 58.4% (CV, 45.4%). For the dose administered IV, t1/2 was 3.7 hours (CV, 52.3%), clearance was 0.588 L/kg/h (CV, 33.9%), and volume of distribution was 2.39 L/kg (CV, 23.7%). After PO administration as a solution versus IV administration, plasma concentrations were more uniform and consistent among dogs, with absorption of 71% (CV, 7.3%), t1/2 of 3.1 hours (CV, 18.6%), and peak plasma concentration of 4.67 μg/mL (CV, 17.6%).
Conclusions and Clinical Relevance—Inconsistent oral absorption of ciprofloxacin in some dogs may be formulation dependent and affected by tablet dissolution in the small intestine. Because of the wide range in oral absorption of tablets, the dose needed to reach the pharmacokinetic-pharmacodynamic target concentration in this study ranged from 12 to 52 mg/kg (CV, 102%), with a mean dose of 25 mg/kg, once daily, for bacteria with a minimum inhibitory concentration ≤ 0.25 μg/mL.
Objective—To investigate the pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or IV infusion of penciclovir.
Procedures—Cats received famciclovir (40 [n = 3] or 90  mg/kg, PO, once) in a balanced crossover-design study; the alternate dose was administered after a ≥ 2-week washout period. After another washout period (≥ 4 weeks), cats received an IV infusion of penciclovir (10 mg/kg delivered over 1 hour). Plasma penciclovir concentrations were analyzed via liquid chromatography-mass spectrometry at fixed time points after drug administration.
Results—Mean ± SD maximum plasma concentration (Cmax) of penciclovir following oral administration of 40 and 90 mg of famciclovir/kg was 1.34 ± 0.33 μg/mL and 1.28 ± 0.42 μg/mL and occurred at 2.8 ± 1.8 hours and 3.0 ± 1.1 hours, respectively; penciclovir elimination half-life was 4.2 ± 0.6 hours and 4.8 ± 1.4 hours, respectively; and penciclovir bioavailability was 12.5 ± 3.0% and 7.0 ± 1.8%, respectively. Following IV infusion of penciclovir (10 mg/kg), mean ± SD penciclovir clearance, volume of distribution, and elimination half-life were 4.3 ± 0.8 mL/min/kg, 0.6 ± 0.1 L/kg, and 1.9 ± 0.4 hours, respectively.
Conclusions and Clinical Relevance—Penciclovir pharmacokinetics following oral administration of famciclovir were nonlinear within the dosage range studied, likely because of saturation of famciclovir metabolism. Oral administration of famciclovir at 40 or 90 mg/kg produced similar Cmax and time to Cmax values. Therefore, the lower dose may have similar antiviral efficacy to that proven for the higher dose.
Objective—To evaluate the impact of modulation of the membrane-bound efflux pump P-glycoprotein (P-gp) on plasma concentrations of orally administered prednisolone in dogs.
Animals—7 healthy adult Beagles.
Procedures—Each dog received 3 treatments (control [no treatment], rifampicin [100 mg/d, PO, for 21 days, as an inducer of P-gp], and ketoconazole [100 mg/d, PO, for 21 days, as an inhibitor of P-gp]). A single dose of prednisolone (1 mg/kg, PO) was administered on day 8 of each treatment period. There was a 7-day washout period between subsequent treatments. Plasma concentrations of prednisolone were determined by use of a validated liquid chromatography–tandem mass spectrometry method. Duodenum and colon biopsy specimens were obtained endoscopically from anesthetized dogs and assessed for P-gp protein labeling via immunohistochemical analysis and mRNA quantification via real-time PCR assay. Total fecal collection was performed for evaluation of effects of P-gp modulation on digestion of nutrients.
Results—Rifampicin treatment upregulated duodenal P-gp in dogs and significantly reduced the area under the plasma concentration-time curve of prednisolone. Ketoconazole typically downregulated expression of duodenal P-gp, with a subsequent increase in the area under the plasma concentration-time curve of prednisolone. There was a noticeable interindividual difference in response. Digestion of nutrients was not affected.
Conclusions and Clinical Relevance—Modulation of P-gp expression influenced plasma concentrations of prednisolone after oral administration in dogs. Thus, treatment response to prednisolone may be influenced by coadministration of P-gp–modulating medications or feed ingredients.
Objective—To determine the pharmacokinetics of a commercial formulation of doxycycline hyclate after IM administration of a single dose to sheep.
Animals—11 healthy domestic sheep.
Procedures—For each sheep, doxycycline was administered as a single dose of 20 mg/kg, IM. Blood samples were obtained prior to and for 84 hours after doxycycline administration. Plasma concentrations of doxycycline were determined via high-performance liquid chromatography with UV detection. Pharmacokinetic data were analyzed with noncompartmental methods.
Results—Mean ± SD values for pharmacokinetic parameters included maximum plasma concentration (2.792 ± 0.791 μg/mL), time to reach maximum plasma concentration (0.856 ± 0.472 hours), mean residence time (91.1 ± 40.78 hours), elimination half-life (77.88 ± 28.45 hours), and area under the curve (65.67 ± 9.877 μg•h/mL).
Conclusions and Clinical Relevance—Results indicated that doxycycline had prolonged absorption and elimination in sheep after IM administration. A daily dose of 20 mg/kg would be sufficient to reach effective plasma concentrations against Chlamydia spp (minimum inhibitory concentration, 0.008 to 0.031 μg/mL) and Staphylococcus aureus (minimum inhibitory concentration, 0.12 μg/mL). Doxycycline administered IM could be an option for therapeutic use in sheep, although further studies are needed.