A pharmacokinetic study of phenobarbital in mature horses after oral dosing

The pharmacokinetics of phenobarbital were determined in six mature horses after a single oral dose. Horses were administered a 5.5 mg/kg of body weight oral dose of phenobarbital tablets. Based on the combined evaluation of i.v. and oral results, phenobarbital displayed two-compartment pharmacokinetics in the horse with a terminal half-life of 19.0 +/- 4.4 (mean +/- SD) h. This half-life is considerably shorter than those reported for dogs and humans. The steady-state volume of distribution (Vdss/F) and the total body clearance (Clt/F) of phenobarbital were 0.753 +/- 0.115 l/kg and 27.9 +/- 9.2 ml/h/kg, respectively. The average extent of oral absorption was 101% with a range of 76 to 124% among the six horses. Examination of the absorption kinetics demonstrated a biphasic absorption process in four horses with a rapid absorption followed by a slower absorption phase. The mean residence time (MRT) was 36.9 +/- 4.1 h and the mean residence time for oral absorption (MRTabs) was 11.3 h. Based on the results of the present study, an oral dosing regimen of 11 mg/kg of body weight every 24 h can be recommended.     

Pharmacokinetics of phenylbutazone in mature Holstein bulls: steady-state kinetics after multiple oral dosing

Six mature Holstein bulls were given an 8-day course of phenylbutazone (PBZ) orally (loading dose, 12 mg of PBZ/kg of body weight and 7 maintenance doses of 6 mg of PBZ/kg, q 24 h). Plasma concentration-vs-time data were analyzed, using nonlinear regression modeling. The harmonic mean +/- pseudo-SD of the biologic half-life of PBZ was 61.8 +/- 12.8 hours. The arithmetic mean +/- SEM of the total body clearance and apparent volume of distribution were 0.0021 +/- 0.0001 L/h/kg and 0.201 +/- 0.009 L/kg, respectively. The predicted mean minimal plasma concentration of PBZ with this dosage regimen was 75.06 +/- 4.05 micrograms/ml. The predicted minimal plasma drug concentration was compared with the observed minimal plasma drug concentration in another group of bulls treated with PBZ for at least 60 days. Sixteen mature Holstein bulls were given approximately 6 mg of PBZ/kg, PO, daily for various musculoskeletal disorders. The mean observed minimal plasma concentration of PBZ in the 16 bulls was 76.10 +/- 2.04 micrograms/ml, whereas the mean predicted minimal plasma concentration was 74.69 +/- 3.10 micrograms/ml. Dosages of 4 to 6 mg of PBZ/kg, q 24 h, or 10 to 14 mg of PBZ/kg, q 48 h, provided therapeutic plasma concentrations of PBZ with minimal steady-state concentrations between 50 and 70 micrograms/ml.     

Multiple oral dosing of valacyclovir in horses and ponies

The aim of the current study was to investigate whether multiple oral dosing of valacyclovir could result in plasma concentrations exceeding the EC₅₀-value of acyclovir against equine herpesvirus 1 (EHV1) during the majority of the treatment period. Additionally, we wanted to determine the concentration of acyclovir in nasal mucus and cerebrospinal fluid (CSF). Valacyclovir was administered to four horses and two ponies, three times daily, at a dosage of 40 mg/kg, for four consecutive days. Blood was collected prior to each administration and 1 h after dosing. Nasal mucus samples and CSF were collected once during treatment; 1 h after the last administration. This dosage regimen resulted in plasma concentrations that were higher than the EC₅₀-value of 1.7 μg/mL, i.e. EC₅₀ of an isolate highly susceptible to acyclovir, for 80% of the treatment period; and higher than the EC₅₀-value of 3.0 μg/mL, i.e. EC₅₀ of an isolate less susceptible to acyclovir, for 60% of the treatment period. Concentration in nasal mucus samples and CSF was 0.36–1.17 μg/mL and 0.11–0.23 μg/mL, respectively. This study illustrates that multiple dosing of valacyclovir may result in a therapeutic benefit as plasma concentrations could be maintained above the EC₅₀-value of acyclovir against EHV1 for more than 50% of the treatment period. Acyclovir could be detected in both nasal mucus samples and CSF. However, these concentrations were lower than the EC₅₀.     

Pharmacokinetics of azithromycin in foals after i.v. and oral dose and disposition into phagocytes

The properties of azithromycin suggest that it may be an alternative to erythromycin for treatment of Rhodococcus equi pneumonia in foals. To investigate this possibility, the disposition of azithromycin in plasma, polymorphonuclear leukocytes (PMN), and alveolar cells was examined after a single administration in foals. Azithromycin suspension was administered orally (p.o.) at a dose of 10 mg/kg to five healthy 2-3-month-old foals. Two weeks later, azithromycin for injection was administered by intravenous (i.v.) infusion at a dose of 5 mg/kg to the same foals. Plasma samples were collected after p.o. and i.v. administration. Peripheral blood PMN and bronchoalveolar lavage fluid and alveolar cells were collected after p.o. administration. Azithromycin concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC) with coulometric electrochemical detection. Azithromycin p.o. absorption was variable with a mean systemic availability of 39% (+/-20%). The plasma half-life was 16 and 18.3 h after i.v. and p.o. administration, respectively. Azithromycin had a very large volume of distribution (V(d)) of 11.6 L/kg [V(d(ss))] and 12.4 L/kg [V(d(area))]. The large V(d) can be attributed to high tissue and intracellular concentrations, exhibited by the high concentration of azithromycin in PMN and alveolar cells. The PMN half-life was 49.2 h. Dosage of 10 mg/kg of azithromycin p.o. once daily for foals with R. equi pneumonia is recommended for further study.     

Pharmacokinetics of phenylbutazone and its metabolite oxyphenbutazone in miniature donkeys

OBJECTIVE: To describe the pharmacokinetics of phenylbutazone and oxyphenbutazone after IV administration in miniature donkeys. ANIMALS: 6 clinically normal miniature donkeys. PROCEDURE: Blood samples were collected before and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 480 minutes after IV administration of phenylbutazone (4.4 mg/kg of body weight). Serum was analyzed in triplicate by use of high-performance liquid chromatography for determination of phenylbutazone and oxyphenbutazone concentrations. The serum concentration-time curve for each donkey was analyzed separately to estimate model-independent pharmacokinetic variables. RESULTS: Serum concentrations decreased rapidly after IV administration of phenylbutazone, and they reached undetectable concentrations within 4 hours. Values for mean residence time ranged from 0.5 to 3.0 hours (median, 1.1 hour), whereas total body clearance ranged from 4.2 to 7.5 ml/kg/min (mean, 5.8 ml/kg/min). Oxyphenbutazone appeared rapidly in the serum; time to peak concentration ranged from 13 to 41 minutes (mean, 26.4 minutes), and peak concentration in serum ranged from 2.8 to 4.0 mg/ml (mean, 3.5 microg/ml). CONCLUSION AND CLINICAL RELEVANCE: Clearance of phenylbutazone in miniature donkeys after injection of a single dose (4.4 mg/kg, IV) is rapid. Compared with horses, miniature donkeys may require more frequent administration of phenylbutazone to achieve therapeutic efficacy.     

Effects of oral cimetidine on plasma concentrations of phenylbutazone in horses

Phenylbutazone was administered to six Thoroughbred horses in a cross-over study in which the horses received cimetidine pretreatment or no cimetidine pretreatment. Blood samples were collected at various times for 48 h after phenylbutazone administration and the plasma was analysed for phenylbutazone. Cimetidine pretreatment elevated phenylbutazone plasma concentrations during the first 8 h after phenylbutazone administration. The absorption rate, maximum phenylbutazone plasma concentrations and AUC were significantly greater with cimetidine pretreatment. The half-life of phenylbutazone did not change with cimetidine pretreatment; however, lower plasma concentrations of the metabolite gamma-hydroxyphenylbutazone were observed with cimetidine pretreatments. Plasma concentrations of the metabolite oxyphenbutazone were unchanged with cimetidine pretreatment compared to control values. Twenty-four-hour plasma concentrations of phenylbutazone were not different from control values with cimetidine pretreatment. This study suggests that concurrent treatment with cimetidine and phenylbutazone 24 h before race time does not result in elevations of plasma phenylbutazone concentrations above control values.     

Pharmacokinetics and bioavailability of spectinomycin after i.v., i.m., s.c. and oral administration in broiler chickens

A pharmacokinetic and bioavailability study of spectinomycin was conducted in healthy broiler chickens following administration of a single (50 mg/kg bw) intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) dose and oral doses of 50 and 100 mg/kg bw. Following i.v. administration, the elimination half-life (t1/2beta), mean residence time (MRT), volume of distribution at steady-state (Vd(ss)), volume of distribution based on the terminal phase (Vd(z)) and total body clearance (ClB) were 1.46+/-1.10 h, 1.61+/-1.05 h, 0.26+/-0.009 L/kg, 0.34 (0.30-0.38) L/kg and 2.68+/-0.017 mL/min/kg respectively. After i.m. and s.c. dosing, the Cmax was 152.76+/-1.08 and 99.77+/-1.04 microg/mL, achieved at 0.25 (0.25-0.50) and 0.25 (0.25-1.00) h, the t1/2beta was 1.65+/-1.07 and 2.03+/-1.06 h and the absolute bioavailability (F) was 136.1% and 128.8% respectively. A significant difference in Cmax (5.13+/-0.10, 14.26+/-1.12 microg/mL), t1/2beta (3.74+/-1.07, 8.93+/-1.13 h) and ClB/F (22.69+/-0.018, 10.14+/-0.018 mL/min/kg) were found between the two oral doses (50 and 100 mg/kg bw respectively), but there were no differences in the tmax [2.00 (2.00-4.00), 2.00 (2.00-2.00) h] and Vd(z)/F [6.95 (6.34-9.06), 7.98 (4.75-10.62) L/kg). The absolute bioavailability (F) of spectinomycin was 11.8% and 26.4% after oral administration of 50 and 100 mg/kg bw respectively.     

Pharmacokinetics and tissue fluid distribution of cephalexin in the horse after oral and i.v. administration

The purpose of this study was to determine the pharmacokinetics and tissue fluid distribution of cephalexin in the adult horse following oral and i.v. administration. Cephalexin hydrate (10 mg/kg) was administered to horses i.v. and plasma samples were collected. Following a washout period, cephalexin (30 mg/kg) was administered intragastrically. Plasma, interstitial fluid (ISF) aqueous humor, and urine samples were collected. All samples were analyzed by high-pressure liquid chromatography (HPLC). Following i.v. administration, cephalexin had a plasma half-life (t(1/2)) of 2.02 h and volume of distribution [V(d(ss))] of 0.25 L/kg. Following oral administration, the average maximum plasma concentration (C(max)) was 3.47 mug/mL and an apparent half-life (t(1/2)) of 1.64 h. Bioavailability was approximately 5.0%. The AUC(ISF):AUC(plasma) ratio was 80.55% which corresponded to the percentage protein-unbound drug in the plasma (77.07%). The t(1/2) in the ISF was 2.49 h. Cephalexin was not detected in the aqueous humor. The octanol:water partition coefficient was 0.076 +/- 0.025. Cephalexin was concentrated in the urine with an average concentration of 47.59 microg/mL. No adverse events were noted during this study. This study showed that cephalexin at a dose of 30 mg/kg administered orally at 8 h dosage intervals in horses can produce plasma and interstitial fluid drug concentrations that are in a range recommended to treat susceptible gram-positive bacteria (MIC < or = 0.5 microg/mL). Because of the low oral bioavailability of cephalexin in the horse, the effect of chronic dosing on the normal intestinal bacterial flora requires further investigation.     

Distribution of voriconazole in seven body fluids of adult horses after repeated oral dosing

Passler, N. H., Chan, H.-M., Stewart, A. J., Duran, S. H., Welles, E. G., Lin, H.-C., Ravis, W. R. Distribution of voriconazole in seven body fluids of adult horses after repeated oral dosing. J. vet. Pharmacol. Therap . 33 , 35–41.
The purpose of this study was to assess safety and alterations in body fluid concentrations of voriconazole in normal horses on days 7 and 14 following once daily dose of 4 mg/kg of voriconazole orally for 14 days. Body fluid drug concentrations were determined by the use of high performance liquid chromatography (HPLC). On day 7, mean voriconazole concentrations of plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, epithelial lining fluid (ELF), and urine were 1.47 ± 0.63, 0.61 ± 0.22, 0.70 ± 0.20, 0.62 ± 0.26, 0.55 ± 0.32, 79.45 ± 69.4, and 1.83 ± 0.44 μg/mL respectively. Mean voriconazole concentrations in the plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, ELF and urine on day 14 were 1.60 ± 0.37, 1.02 ± 0.27, 0.86 ± 0.25, 0.64 ± 0.21, 0.68 ± 0.13, 47.76 ± 45.4 and 3.34 ± 2.17 respectively. Voriconazole concentrations in the bronchoalveolar cell pellet were below the limit of detection. There was no statistically significant difference between voriconazole concentrations of body fluids when comparing days 7 and 14. Results indicated that voriconazole distributes widely into body fluids.     

Effects of oral administration of phenylbutazone to horses on in vitro articular cartilage metabolism.

OBJECTIVE: To evaluate the effects of orally administered phenylbutazone on proteoglycan synthesis and chondrocyte inhibition by IL-1beta in articular cartilage explants of horses. ANIMALS: 11 healthy 1- to 2-year-old horses. PROCEDURE: Horses were randomly assigned to the control (n = 5) or treated group (4.4 mg of phenylbutazone/kg of body weight, p.o., q 12 h; n = 6). Articular cartilage specimens were collected before treatment was initiated (day 0), after 14 days of treatment, and 2 weeks after cessation of treatment (day 30). Proteoglycan synthesis and stromelysin concentration in cartilage extracts were assessed after 72 hours of culture in medium alone or with recombinant human interleukin-1beta (IL-1beta; 0.1 ng/ml). RESULTS: On day 0, proteoglycan synthesis was significantly less in cartilage explants cultured in IL-1beta, compared with medium alone. Mean proteoglycan synthesis in explants collected on days 14 and 30 was significantly less in treated horses, compared with controls. However, incubation of explants from treated horses with IL-1beta did not result in a further decrease in proteoglycan synthesis. Significant differences in stromelysin concentration were not detected between or within groups. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of phenylbutazone for 14 days significantly decreased proteoglycan synthesis in articular culture explants from healthy horses to a degree similar to that induced by in vitro exposure to IL-1beta. Phenylbutazone should be used judiciously in athletic horses with osteoarthritis, because chronic administration may suppress proteoglycan synthesis and potentiate cartilage damage.     

Pharmacokinetics of azithromycin after i.v. and i.m. administration to sheep

The pharmacokinetics (PK) of azithromycin after i.v. and i.m. injection at a single dosage of 20 mg/kg bodyweight was studied in sheep. Blood samples were collected from the jugular vein until 120 h after dosing for both routes. Plasma concentrations of azithromycin were determined by bioassay. The plasma concentration-time data of azithromycin best fitted a three-compartment model after i.v. administration and a two-compartment model with first-order absorption after i.m. administration. The elimination half-life (t(1/2lambdaz)) was 47.70 +/- 7.49 h after i.v. administration and 61.29 +/- 13.86 h after i.m. administration. Clearance value after i.v. dosing was 0.52 +/- 0.08 L/kg.h. After i.m. administration a peak azithromycin concentration (C(max)) of 1.26 +/- 0.19 mg/L was achieved at 1.24 +/- 0.31 h (t(max)). Area under the curve (AUC) were 38.85 +/- 5.83 mg.h/L and 36.03 +/- 1.52 mg.h/L after i.v. and i.m. administration respectively. Bioavailability obtained after i.m. administration was 94.08 +/- 11.56%. The high tolerability of this i.m. preparation and the favourable PK behaviour such as the long half-life and high bioavailability make azithromycin likely to be effective in sheep.     

Comparative pharmacokinetics and bioavailability of tylosin tartrate and tylosin phosphate after a single oral and i.v. administration in chickens

The pharmacokinetics and oral bioavailability of tylosin tartrate and tylosin phosphate were carried out in broiler chickens according to a principle of single dose, random, parallel design. The two formulations of tylosin were given orally and intravenously at a dose level of 10 mg/kg b.w to chicken after an overnight fasting (n = 10 chickens/group). Serial blood samples were collected at different time points up to 24 h postdrug administration. A high performance liquid chromatography method was used for the determination of tylosin concentrations in chicken plasma. The tylosin plasma concentration's time plot of each chicken was analyzed by the 3P97 software. The pharmacokinetics of tylosin was best described by a one‐compartmental open model 1st absorption after oral administration. After intravenous administration the pharmacokinetics of tylosin was best described by a two‐compartmental open model, and there were no significant differences between tylosin tartrate and tylosin phosphate. After oral administration, there were significant differences in the C_max (0.18 ± 0.01, 0.44 ± 0.09) and AUC (0.82 ± 0.05, 1.57 ± 0.25)between tylosin phosphate and tylosin tartrate. The calculated oral bioavailability (F) of tylosin tartrate and tylosin phosphate were 25.78% and 13.73%, respectively. Above all, we can reasonably conclude that, the absorption of tylosin tartrate is better than tylosin phosphate after oral administration.     

Plasma and serum concentrations of phenylbutazone and oxyphenbutazone in racing Thoroughbreds 24 hours after treatment with various dosage regimens

The plasma and serum concentrations of phenylbutazone (PBZ) and oxyphenbutazone were measured in 158 Thoroughbred horses after various doses of PBZ wer given. All horses were competing or training at racetracks in various parts of the country. All horses used in the study had not been given PBZ 24 hours before they were placed on a specific dosage schedule. Samples were collected 24 hours after the last PBZ administration. Four grams of PBZ were given daily by stomach tube, paste, or tablet for 3 days. On day 4, 24 hours before sample collection, an IV dose of 2 g of PBZ was given, regardless of the dose and method of administration. The 24-hour PBZ plasma concentrations were 3.51, 6.13, and 6.40 micrograms/ml, respectively. After 2 g of PBZ was administered IV daily for 4 days, the plasma PBZ concentration was 4.16 g/ml; after a single 2-g IV administration, the serum concentration was 0.87 g/ml. Concentrations of oxyphenbutazone were 3.35 (stomach tube), 4.29 (paste), 3.60 (tablet), 3.65 (4-day IV), and 1.11 g/ml (single IV). A significant relationship was not found between the serum and the urinary concentrations at this 24-hour measurement. Split samples sent to various laboratories confirmed the stability of high-performance liquid chromatography as a method of analysis.