Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim following intravenous, intramuscular and oral administration in ostriches (Struthio camelus)

A pharmacokinetic and bioavailability study of sulfadiazine combined with trimethoprim (sulfadiazine/trimethoprim) was carried out in fifteen healthy young ostriches after intravenous (i.v.), intramuscular (i.m.) and oral administration at a total dose of 30 mg/kg body weight (bw) (25 and 5 mg/kg bw of sulfadiazine and trimethoprim, respectively). The study followed a single dose, three periods, cross‐over randomized design. The sulfadiazine/trimethoprim combination was administered to ostriches after an overnight fasting on three treatment days, each separated by a 2‐week washout period. Blood samples were collected at 0 (pretreatment), 0.08, 0.25, 0.50, 1, 2, 4, 6, 8, 12, 24 and 48 h after drug administration. Following i.v. administration, the elimination half‐life (t_1/2β), the mean residence time (MRT), volume of distribution at steady‐state (V_d(ss)), volume of distribution based on terminal phase (V_d(z)), and the total body clearance (Cl_B) were (13.23 ± 2.24 and 1.95 ± 0.19 h), (10.06 ± 0.33 and 2.17 ± 0.20 h), (0.60 ± 0.08, and 2.35 ± 0.14 L/kg), (0.79 ± 0.12 and 2.49 ± 0.14 L/kg) and (0.69 ± 0.03 and 16.12 ± 1.38 mL/min/kg), for sulfadiazine and trimethoprim, respectively. No significant difference in C_max (35.47 ± 2.52 and 37.50 ± 3.39 μg/mL), t_max (2.47 ± 0.31 and 2.47 ± 0.36 h), t_½β (11.79 ± 0.79 and 10.96 ± 0.56 h), V_d(z)/F (0.77 ± 0.06 and 0.89 ± 0.07 L/kg), Cl_B/F (0.76 ± 0.04 and 0.89 ± 0.07) and MRT (12.39 ± 0.40 and 12.08 ± 0.36 h) were found in sulfadiazine after i.m. and oral dosing, respectively. There were also no differences in C_max (0.71 ± 0.06 and 0.78 ± 0.10 μg/mL), t_max (2.07 ± 0.28 and 3.27 ± 0.28 h), t_½β (3.30 ± 0.25 and 3.83 ± 0.33 h), V_d(z)/F (6.2 ± 0.56 and 6.27 ± 0.77 L/kg), Cl_B/F (21.9 ± 1.46 and 18.83 ± 1.72) and MRT (3.68 ± 0.19 and 4.34 ± 0.14 h) for trimethoprim after i.m. and oral dosing, respectively. The absolute bioavailability (F) was 95.41% and 86.20% for sulfadiazine and 70.02% and 79.58% for trimethoprim after i.m. and oral administration, respectively.     

Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean ± SD): AUC_(0–∞) 4.20 ± 1.66 μg·h/mL; C_max 6.64 ± 1.38 μg/mL; V_z 4.80 ± 0.91 L/kg; Cl_t 2.64 ± 0.84 L/h·kg; t_½λ 1.35 ± 0.40 h and MRT 1.50 ± 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean ± SD): C_max, 0.30 ± 0.17 and 0.17 ± 0.09 μg/mL; t_max, 1.75 ± 0.76 and 0.69 ± 0.30 h; t_½λ, 2.92 ± 0.79 and 1.53 ± 1.28 h and MRT, 5.10 ± 1.12 and 2.56 ± 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC₉₀ = 0.5 μg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.     

Pharmacokinetics of allopurinol in Dalmatian dogs

The pharmacokinetics of allopurinol were studied in Dalmatian dogs. Eight dogs were given allopurinol orally at a dose of 10 mg/kg for seven doses prior to sample collection. After a period of at least two weeks, four of these dogs and four additional Dalmatians were later given a single intravenous (i.v.) dose of allopurinol (6 mg/kg) prior to sample collection.Allopurinol was found to follow first-order absorption and elimination kinetics. In the i.v. kinetic study, the elimination constant (K_el) = 0.31±0.03 per h, the half-life (t_½) = 2.22±0.20 h, the initial concentration (C₀) = 5.26±0.34 μg/mL and the specific volume (V_d) = 1.14±0.07 L/kg. Clearance of allopurinol was estimated to be 0.36±0.03 L/kg·h. In the oral kinetic study, the absorption rate constant (K_ab) = 1.06±0.13 per h, the elimination rate constant (K_el) = 0.26±0.01 per h, the absorption half-life (t_½ab) = 0.66±0.06 h, and the elimination half-life (t_½el) = 2.69±0.14 h. Peak plasma concentrations (C_max) = 6.43±0.18 μg/mL were obtained within 1 to 3 h (mean time of maximum concentration (T_max) = 1.9±0.1 h). The volume of distribution corrected by the fraction of dose absorbed (V_d/F) was estimated to be 1.17±0.07 L/kg.Good agreement was obtained between mean kinetic parameters in the oral and i.v. studies. There was little variation between individual dogs in the i.v. study, whereas the rate of absorption and elimination of orally administered allopurinol was more varied among individual dogs. Because of this, and the fact that the magnitude of hyperuricosuria varies among Dalmatians, it is not possible to specify an exact dose of allopurinol that will effectively lower the urinary uric acid concentration to acceptable values in all Dalmatians with hyperuricosuria; rather, the dose must be titrated to the needs of each dog.     

The effects on the pharmacokinetics of intravenous ceftiofur sodium in dairy cattle of simultaneous intravenous acetyl salicylate (aspirin) or probenecid

Ceftiofur sodium is a third-generation cephalosporin antibiotic. It is possible that non-steroidal anti-inflammatory drugs such as acetyl salicylate (aspirin) may be used concomitantly with ceftiofur sodium in dairy cattle. Therefore this study evaluated potential pharmacokinetic interactions between ceftiofur sodium and aspirin. In addition, this study evaluated the potential for interaction between ceftiofur and its active metabolites and the organic anion transporter. The organic anion transporter substrate used in this evaluation was probenecid. Ten healthy, non-pregnant, non-lactating dairy cows were used in a randomized complete three-way crossover design. In repeated experiments all cows were administered: (1) 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (2) 10 mg of probenecid per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus or (3) 26 mg of aspirin per kg body weight by intravenous bolus, followed immediately by 2 mg of ceftiofur sodium per kg body weight by intravenous bolus. For treatment with ceftiofur sodium alone, the mean volume of distribution at steady-state V_d(33) was 0.2 ± 0.06 L/kg, the mean volume of distribution by the area method V_d(area) was 0.38 ± 0.22 L/kg, mean residence time (MRT) was 6.5 ± 1.8 h, mean residence time in peripheral tissues (MRT_p) was 2.6 ± 1.0 h, total body clearance (Cf) was 0.032 ± 0.013 L/kg/h and elimination rate constant (P) was 0.097 ± 0.044 h^-1(mean ± standard deviation). No statistically significant changes were detected as a result of preceding treatment with aspirin. Preceding treatment with probenecid resulted in a decrease in both Cl (0.007 ± 0.005 L/kg/h) and MRT_p (0.89 ± 0.45 h). These results suggest that ceftiofur or its metabolites may interact with the organic anion transporter, but that consideration of alterations to dose and dose interval may not be necessary when ceftiofur sodium is administered to the cow concomitantly with a single dose of aspirin.     

Pharmacokinetics of Tilmicosin (Provitil Powder and Pulmotil Liquid AC) Oral Formulations in Chickens

A bioavailability and pharmacokinetics study of powder and liquid tilmicosin formulations was carried out in 18 healthy chickens according to a single-dose, two-period, two-sequence, crossover randomized design. The two formulations were Provitil and Pulmotil AC. Both drugs were administered to each chicken after an overnight fast on two treatment days separated by a 2-week washout period. A modified rapid and sensitive HPLC method was used for determination of tilmicosin concentrations in chicken plasma. Various pharmacokinetic parameters including area under plasma concentration–time curve (AUC₀₋₇₂), maximum plasma concentration (C _max), time to peak concentration (t _max), elimination half-life (t _1/2β), elimination rate (k _el), clearance (Cl_B), mean residence time (MRT) and volume of distribution (V _d,area) were determined for both formulations. The average means of AUC₀₋₇₂ for Provitil and Pulmotil AC were very close (24.24 ± 3.86, 21.82 ± 3.14 (μg.h)/ml, respectively), with no significant differences based on ANOVA. The relative bioavailability of Provitil as compared to Pulmotil AC was 111%. In addition, there were no significant differences in the C _max (2.09 ± 0.37, 2.12 ± 0.40 μg/ml), t _max (3.99 ± 0.84, 5.82 ± 1.04 h), t _1/2β (47.4 ± 9.32, 45.0 ± 5.73 h), k _el (0.021 ± 0.0037, 0.022 ± 0.0038 h⁻¹), Cl_B (19.73 ± 3.73, 21.37 ± 4.54 ml/(min/kg)), MRT (71.20 ± 12.87, 67.15 ± 9.01 h) and V _d,area (1024.8 ± 87.5, 1009.8 ± 79.5 ml/kg) between Pulmotil AC and Provitil, respectively. In conclusion, tilmicosin was rapidly absorbed and slowly eliminated after oral administration of single dose of tilmicosin aqueous and powder formulations. Provitil and Pulmotil AC can be used as interchangeable therapeutic agents.     

Pharmacokinetics of the novel COX‐2 selective inhibitor vitacoxib in cats: The effects of feeding and dose

The purpose of this study was to determine the pharmacokinetics and dose‐scaling model of vitacoxib in either fed or fasted cats following either oral or intravenous administration. The concentration of the drug was quantified by UPLC‐MS/MS on plasma samples. Relevant parameters were described using noncompartmental analysis (WinNonlin 6.4 software). Vitacoxib is relatively slowly absorbed and eliminated after oral administration (2 mg/kg body weight), with a T_max of approximately 4.7 hr. The feeding state of the cat was a statistically significant covariate for both area under the concentration versus time curve (AUC) and mean absorption time (MAT_fed). The absolute bioavailability (F) of vitacoxib (2 mg/kg body weight) after oral administration (fed) was 72.5%, which is higher than that in fasted cats (F = 50.6%). Following intravenous administration (2 mg/kg body weight), Vd (ml/kg) was 1,264.34 ± 343.63 ml/kg and Cl (ml kg^?1 hr^?1) was 95.22 ± 23.53 ml kg^?1 hr^?1. Plasma concentrations scaled linearly with dose, with C_max (ng/ml) of 352.30 ± 63.42, 750.26 ± 435.54, and 936.97 ± 231.27 ng/ml after doses of 1, 2, and 4 mg/kg body weight, respectively. No significant undesirable behavioral effects were noted throughout the duration of the study.     

Pharmacokinetic–pharmacodynamic modelling of meperidine in goats (I): pharmacokinetics

Qiao, G.-L., Fung, K.-F. Pharmacokinetic-pharmacodynamic modelling of meperidine in goats (I): pharmacokinetics. J. vet. Pharmacol. Therap. 16 , 426–437. Plasma and cerebrospinal fluid (CSF) pharmacokinetics of meperidine were investigated after intramuscular (i.m.) or intravenous (i.v.) administration at a dose of 5 mg/kg in adult goats. After i.m. dosing, the plasma profile was best described by a one-compartment open model. In healthy (n = 16) and postoperative (n = 16) goats, the parameters were, respectively: /_max 8.3 ± 3.9 and 9.2 ± 5.5 min, V_d 2.763 ±1.231 and 3.929 ±2.101 1/kg, Cl_b 0.125 ± 0.036 and 0.087 ± 0.025 1/kg/min, K_c 0.0563 ± 0.0358 and 0.0271 ± 0.0136 min^-1. The plasma profile was best fitted by a two-compartment open model following i.v. injection. In this case, the parameters for healthy (n= 7) and post-operative (n= 13) goats were, respectively: V_d 5.212 ± 1.992 and 5.085 ± 2.288 1/kg, Cl_b 0.096 ± 0.028 and 0.075 ± 0.026 1/kg/min, P 0.0211 ± 0.0093 and 0.0160 ± 0.0052 min.^-1. There were, however, a few individuals with a prolonged elimination phase. Bioavailability of i.m. meperidine was 66.5 ± 15.8% in healthy (n= 6) goats, but much higher in postoperative (n = 10) ones at 94.6 ± 30.0%. Meperidine diffused into and out of CSF according to a first-order rate process. The time-course of CSF drug concentration was simulated by a biexponential function. CSF kinetic parameters of i.m. meperidine for healthy (n = 7) and postoperative (n = 13) goats were: elimination rate constant (K_ei) 0.0269 ± 0.0131 and 0.0305 ± 0.0177 min“¹, peak CSF concentration time (T_naxl) 15.9 ± 5.0 and 17.0 ± 6.9 min. For the i.v. dosed healthy (n = 6) and postoperative (n = 8) animals, K_el was 0.0408 ± 0.0107, 0.0414 ± 0.0123 min^-1 and 7_maxt was 10.0 ± 5.0 and 7.7 ± 2.5 min, respectively. It was demonstrated that an obviously lower peak concentration can be reached significantly later in CSF than in plasma, and the kinetic behaviour of meperidine in plasma is different from that in the CSF, indicating meperidine analgesia might not be predicted by simple extrapolation from the kinetic data.     

Oral absorption and bioavailability of flumequine in veal calves

Summary

The oral absorption and bioavailability of flumequine was studied in 1‐, 5‐ and 18‐week‐old calves following intravenous and oral administration of different formulations of flumequine (Flumix^®, Flumix C^® and pure flumequine). Increasing age had a negative influence on the C_max after the administration of Flumix^®, based on a larger V_D in the older calves. The C_max decreased from 5.02 ± 1.46 μg/ml in the first week to 3.28 ± 0.42 μg/ml in the 18th week. Adding colistin sulfate to the flumequine formulation and administring pure flumequine mixed with milk replacer had a negative effect on the C_max of flumequine after oral administration of 5 and 10 mg/kg body weight. The bioavailability of the orally administered flumequine formulations was 100% in all cases except after the administration of Flumix C^®, for which it was 75.9 ± 18.2%. The urinary recovery of flumequine after intravenous injection of a 10% solution varied from 35.2 ± 2.3% for Group B. to 41.2 ± 6.3% for Group C.

The dosage of 5 mg/kg body weight Flumix^® twice daily in 1‐week‐old veal calves is sufficient to reach therapeutic plasma concentrations, based on a MIC value of 0.8 μg/ml of the target bacteria.

In older calves it is advisable to increase the dosage 7.5 or 10 mg/kg body weight every 12 hours. In combination with colistin sulfate it is also advisable to increase the dosage slightly because of the negative effect of the colistin sulfate on the C_max of flumequine.     

Pharmacokinetics of doxycycline in laying hens after intravenous and oral administration

1. The pharmacokinetics of doxycycline in laying hens was investigated after a single intravenous (IV) or an oral (PO) dose at 20 mg/kg body weight.

2. The concentrations of doxycycline in plasma samples were determined by high-performance liquid chromatography with an ultraviolet detector, and pharmacokinetic parameters were calculated using a compartmental model method.

3. The disposition of doxycycline after one single IV injection was best described by a two-compartment open model and the main pharmacokinetic parameters were as follows: volume of distribution (V_d) was 865.15 ± 127.64 ml/kg, distribution rate constant (α) was (2.28 ± 0.38) 1/h, elimination rate constant (β) was 0.08 ± 0.02 1/h and total body clearance (Cl) was104.11 ± 18.32 ml/h/kg, while after PO administration, the concentration versus time curve was best described by a one-compartment open model and absorption rate constant (K_a), peak concentration (C_max), time to reach C_max (t_max) and absolute bioavailability (F) were 2.55 ± 1.40 1/h, 5.88 ± 0.70 μg/ml, 1.73 ± 0.75 h and 52.33%, respectively.

4. The profile of doxycycline exhibited favourable pharmacokinetic characteristics in laying hens, such as quick absorption and slow distribution and elimination, though oral bioavailability was relatively low. A multiple-dosing regimen (a dose of 20 mg/kg/d for 3 consecutive days) of doxycycline was recommended to treat infections in laying hens. But a further study should be conducted to determine the withdrawal time of doxycycline in eggs.

     

Pharmacokinetics of doxycycline in sheep after intravenous and oral administration

The pharmacokinetics of doxycycline were investigated in sheep after oral (PO) and intravenous (IV) administration. The IV data were best described using a 2- (n = 5) or 3- (n = 6) compartmental open model. Mean pharmacokinetic parameters obtained using a 2-compartmental model included a volume of distribution at steady-state (V_ss) of 1.759 ± 0.3149 L/kg, a total clearance (Cl) of 3.045 ± 0.5264 mL/kg/min and an elimination half-life (t_1/2β) of 7.027 ± 1.128 h. Comparative values obtained from the 3-compartmental mean values were: V_ss of 1.801 ± 0.3429 L/kg, a Cl of 2.634 ± 0.6376 mL/kg/min and a t_1/2β of 12.11 ± 2.060 h. Mean residence time (MRT_0−∞) was 11.18 ± 3.152 h. After PO administration, the data were best described by a 2-compartment open model. The pharmacokinetic parameter mean values were: maximum plasma concentration (C_max), 2.130 ± 0.950 μg/mL; time to reach C_max (t_max), 3.595 ± 3.348 h, and absorption half-life (t_1/2k01), 36.28 ± 14.57 h. Non-compartmental parameter values were: C_max, 2.182 ± 0.9117 μg/mL; t_max, 3.432 ± 3.307 h; F, 35.77 ± 10.20%, and mean absorption time (MAT_0–∞), 25.55 ± 15.27 h. These results suggest that PO administration of doxycycline could be useful as an antimicrobial drug in sheep.     

Pharmacokinetics of gatifloxacin in broiler chickens following intravenous and oral administration

1. The pharmacokinetics of gatifloxacin were investigated following intravenous and oral administration of a single dose at a rate of 10?mg/kg body weight in broiler chicks.

2. Drug concentration in plasma was determined using High Performance Liquid Chromatography with ultraviolet detection on samples collected at frequent intervals after drug administration.

3. Following intravenous administration, the drug was rapidly distributed (t_1/2α: 0·33?±?0·008?h) and eliminated (t_1/2β: 3·62?±?0·03?h; Cl_B: 0·48?±?0·002?l/h/kg) from the body.

4. After oral administration, the drug was rapidly absorbed (C _max: 1·74?±?0·024?µg/mL; T _max: 2?h) and slowly eliminated (t_1/2β: 3·81?±?0·07?h) from the body. The apparent volume of distribution (V_d(area)), total body clearance (Cl_B) and mean residence time (MRT) were 3·61?±?0·04?l/kg, 0·66?±?0·01?l/h/kg and 7·16?±?0·08?h, respectively. The oral bioavailability of gatifloxacin was 72·96?±?1·10 %.

5. Oral administration of gatifloxacin at 10?mg/kg is likely to be highly efficacious against susceptible bacteria in broiler chickens.     

Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4 mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4 mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2 mg/kg, area under the concentration–time curve (AUC_0−∞), elimination half-life (t_1/2ʎz), total clearance (Cl_T) and volume of distribution at steady state (V_dss) were 6.64 ± 0.81 hr^*µg/ml, 1.57 ± 0.14 hr, 0.30 ± 0.04 L h^-1 kg^-1 and 0.40 ± 0.05 L/kg, respectively. After the administration of TA at a dose of 4 mg/kg showed prolonged t_1/2ʎz, increased dose-normalized AUC_0-∞, and decreased Cl_T. In goats, TA at 4 mg/kg dose can be administered wider dose intervals compared to the 2 mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.     

The intravenous and oral pharmacokinetics of afoxolaner and milbemycin oxime when used as a combination chewable parasiticide for dogs

The pharmacokinetics of afoxolaner and milbemycin oxime (A3 and A4 forms) in dogs were evaluated following the oral administration of NexGard Spectra ^® (Merial), a fixed combination chewable formulation of these two active pharmaceutical ingredients. Absorption of actives was rapid at levels that provide the minimum effective doses of 2.5 mg/kg and 0.5 mg/kg of afoxolaner and milbemycin oxime, respectively. The time to maximum afoxolaner plasma concentrations (t_max) was 2–4 h. The milbemycin t_max was 1–2 h. The terminal plasma half‐life (t_1/2) and the oral bioavailability were 14 ± 3 days and 88.3% for afoxolaner, 1.6 ± 0.4 days and 80.5% for milbemycin oxime A3 and 3.3 ± 1.4 days and 65.1% for milbemycin oxime A4. The volume of distribution (V_d) and systemic clearance (Cls) were determined following an IV dose of afoxolaner or milbemycin oxime. The V_d was 2.6 ± 0.6, 2.7 ± 0.4 and 2.6 ± 0.6 L/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The Cls was 5.0 ± 1.2, 75 ± 22 and 41 ± 12 mL/h/kg for afoxolaner, milbemycin oxime A3 and milbemycin oxime A4, respectively. The pharmacokinetic profile for the combination of afoxolaner and milbemycin oxime supports the rapid onset and a sustained efficacy for afoxolaner against ectoparasites and the known endoparasitic activity of milbemycin oxime.     

Pharmacokinetics of vitacoxib in rabbits after intravenous and oral administration

This study describes the pharmacokinetics of vitacoxib in healthy rabbits following administration of 10 mg/kg intravenous (i.v.) and 10 mg/kg oral. Twelve New Zealand white rabbits were randomly allocated to two equally sized treatment groups. Blood samples were collected at predetermined times from 0 to 36 hr after treatment. Plasma drug concentrations were determined using UPLC‐MS/MS. Pharmacokinetic analysis was completed using noncompartmental methods via WinNonlin^? 6.4 software. The mean concentration area under curve (AUC_last) for vitacoxib was determined to be 11.0 ± 4.37 μg hr/ml for i.v. administration and 2.82 ± 0.98 μg hr/ml for oral administration. The elimination half‐life (T_1/2λz) was 6.30 ± 2.44 and 6.30 ± 1.19 hr for the i.v. and oral route, respectively. The C_max (maximum plasma concentration) and T_max (time to reach the observed maximum (peak) concentration at steady‐state) following oral application were 189 ± 83.1 ng/ml and 6.58 ± 3.41 hr, respectively. Mean residence time (MRT_last) following i.v. injection was 6.91 ± 3.22 and 11.7 ± 2.12 hr after oral administration. The mean bioavailability of oral administration was calculated to be 25.6%. No adverse effects were observed in any rabbit. Further studies characterizing the pharmacodynamics of vitacoxib are required to develop a formulation of vitacoxib for rabbits.     

A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog

Guyonnet, J., Elliott, J., Kaltsatos, V. A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog. J. vet. Pharmacol. Therap. 33 , 260–267. Fifteen Beagle dogs were used to describe the anti‐aldosterone effect of spironolactone (0, 0.8, 2 and 8 mg/kg) in a hyperaldosteronism model. The magnitude of the aldosterone response observed in this model was very similar to the one described in a dog with congestive heart failure (CHF). Each dog was allocated to a treatment group according to a 5 × 5 Latin square crossover design for five periods with a washout period of 7 days between each period. A maximal possible effect (E_max) model was employed to determine the basic pharmacodynamic parameters of spironolactone, measured by high‐performance liquid chromatography, in antagonizing the renal effects of aldosterone. The change in urinary sodium/potassium ratio in response to a single dose of aldosterone was calculated. The inhibition of this response by oral spironolactone administration was assessed. Aldosterone alone decreased sodium excretion by approximately 35% and urinary potassium concentrations increased by 25%, whereas the urine volume decreased, as expected. The effect of aldosterone on the Na⁺/K⁺ ratio was completely reversed (88% inhibition) at a dose of 2 mg spironolactone/kg, while at the dose of 0.8 mg/kg, partial reversal was seen (27.5% inhibition). Urine flow rate was not significantly modified by either aldosterone treatment or aldosterone with spironolactone. The dose of spironolactone required to inhibit the action of aldosterone by 50% (ED₅₀) was estimated to be 1.08 ± 0.28 mg/kg. The E_max was a ratio of 1.089 ± 0.085, close to the observed value in negative control group (1.00 ± 0.18). The proposed spironolactone dose using this E_max model was 2 mg/kg b.w. once daily for the management.     

Pharmacokinetics and dynamics of mycophenolate mofetil after single‐dose oral administration in juvenile dachshunds

Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young‐aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose‐bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole‐blood mitogen‐stimulated T‐cell proliferation was determined using a flow cytometric assay. Plasma MPA C_max (mean ± SD, 9.33 ± 7.04 μg/ml) occurred at <1 hr. The AUC_0–∞ (mean ± SD, 12.84±6.62 hr*μg/ml), MRT_inf (mean ± SD, 11.09 ± 9.63 min), T1/2 (harmonic mean ± PseudoSD 5.50 ± 3.80 min), and k/d (mean ± SD, 0.002 ± 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets.     

Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs

The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC‐MS/MS following an oral zebularine dose of 8 or 4 mg kg^?1. Plasma zebularine clearance was constant. Mean maximum concentration (C_max) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg^?1, respectively. Mean half‐life was 5.7 ± 0.84 and 7.1 ± 2.1 following 8 and 4 mg kg^?1, respectively. A single 8 mg kg^?1 dose was well tolerated. Daily 4 mg kg^?1 treatment in three laboratory dogs resulted in grade 4 neutropenia (n = 3), grade 1 anorexia (n = 2) and grade 1 or 2 dermatologic changes (n = 2). All adverse events resolved with supportive care. A 4 mg kg^?1 dose every 21 days was well tolerated. A follow‐up dose escalation study is in progress with a lower starting dose.     

Florfenicol pharmacokinetics in healthy adult alpacas after subcutaneous and intramuscular injection

Holmes, K., Bedenice, D., Papich, M. G. Florfenicol pharmacokinetics in healthy adult alpacas after subcutaneous and intramuscular injection. J. vet. Pharmacol. Therap.  35 , 382–388. A single dose of florfenicol (Nuflor^®) was administered to eight healthy adult alpacas at 20 mg/kg intramuscular (i.m.) and 40 mg/kg subcutaneous (s.c.) using a randomized, cross‐over design, and 28‐day washout period. Subsequently, 40 mg/kg florfenicol was injected s.c. every other day for 10 doses to evaluate long‐term effects. Maximum plasma florfenicol concentrations (C_max, measured via high‐performance liquid chromatography) were achieved rapidly, leading to a higher C_max of 4.31 ± 3.03 μg/mL following administration of 20 mg/kg i.m. than 40 mg/kg s.c. (C_max: 1.95 ± 0.94 μg/mL). Multiple s.c. dosing at 48 h intervals achieved a C_max of 4.48 ± 1.28 μg/mL at steady state. The area under the curve and terminal elimination half‐lives were 51.83 ± 11.72 μg/mL·h and 17.59 ± 11.69 h after single 20 mg/kg i.m. dose, as well as 99.78 ± 23.58 μg/mL·h and 99.67 ± 59.89 h following 40 mg/kg injection of florfenicol s.c., respectively. Florfenicol decreased the following hematological parameters after repeated administration between weeks 0 and 3: total protein (6.38 vs. 5.61 g/dL, P < 0.0001), globulin (2.76 vs. 2.16 g/dL, P < 0.0003), albumin (3.61 vs. 3.48 g/dL, P = 0.0038), white blood cell count (11.89 vs. 9.66 × 10³/μL, P < 0.044), and hematocrit (27.25 vs. 24.88%, P < 0.0349). Significant clinical illness was observed in one alpaca. The lowest effective dose of florfenicol should thus be used in alpacas and limited to treatment of highly susceptible pathogens.     

The pharmacokinetics of moxidectin following intravenous and topical administration to swine

The pharmacokinetic parameters of moxidectin (MXD) after intravenous and pour‐on (topical) administration were studied in sixteen pigs at a single dose of 1.25 and 2.5 mg/kg BW (body weight), respectively. Blood samples were collected at pretreatment time (0 hr) over 40 days. The plasma kinetics were analyzed by WinNonlin 6.3 software through a noncompartmental model. For intravenous administration (n = 8), the elimination half‐life (λ_Z), the apparent volume of distribution (V_z), and clearance (Cl) were 10.29 ± 1.90 days, 89.575 ± 29.856 L/kg, and 5.699 ± 2.374 L/kg, respectively. For pour‐on administration (n = 8), the maximum plasma drug concentration (C_max), time to maximum plasma concentration (T_max), and λ_Z were 7.49 ng/ml, 1.72, and 6.20 days, respectively. MXD had a considerably low absolute pour‐on bioavailability of 9.2%, but the mean residence time (MRT) for pour‐on administration 10.88 ± 1.75 days was longer than 8.99 ± 2.48 days for intravenous administration. These results showed that MXD was absorbed via skin rapidly and eliminated slowly. The obtained data might contribute to refine the dosage regime for topical MXD administration.