Pharmacokinetics of the amoxicillin–clavulanic acid combination after intravenous and oral administration in cats

The pharmacokinetic properties of amoxicillin (AMX) and clavulanic acid (CLV) were studied in healthy cats following single intravenous and oral dosage of 10 mg/kg of AMX and 2.5 mg/kg of CLV. The drug concentrations in plasma were determined by a high‐performance liquid chromatographic – tandem mass spectrometry (LC‐MS‐MS) method validated for canine plasma and further subjected to noncompartmental analysis. After intravenous injection, no significant difference (p > 0.05) was found in the volume of distribution of these two compounds. In addition, AMX and CLV were both rapidly eliminated from plasma with a clearance of 0.453 and 0.921 L hr^?1 kg^?1, respectively; however, a quicker elimination was observed for CLV (p < 0.01). After oral administration, both drugs were characterized by rapid absorption with an absorption half‐life of 1.10 and 0.70 hr for AMX and CLV, respectively. Significant differences were observed between their absorption rates (p < 0.05). However, the oral bioavailabilities of AMX and CLV (75.57% and 98.15%, respectively) were not statistically different (p > 0.05). A total intravenous or oral dose at 12.5 mg/kg of AMX and CLV (4:1) is predicted to be effective for treating those bacterial species isolated from cats with a minimum inhibitory concentration (MIC) of ≤0.25 μg/ml for 12 hr, based on a time above the MIC (T > MIC) of 40%.     

Pharmacokinetics of fluconazole in cats after intravenous and oral administration

Fluconazole (100 mg) was administered to six adult cats as an intravenous infusion over 30 minutes, and the same cats received 100 mg of the drug orally 16 weeks later. The cats were bled repeatedly through an indwelling jugular catheter, the plasma fluconazole concentrations were assayed by high performance liquid chromatography, and the concentration-time data were subjected to a non-compartmental pharmacokinetic analysis. The mean (SD) intravenous half-life (13·8 [2·6] hours) was similar to that observed after oral dosing (12·4 [3·0] hours). The plasma clearances (intravenous 0·9 [0·1], oral 0·9 [0·2] ml min⁻¹ kg⁻¹) and the volumes of distribution at steady state (intravenous 1·1 [0·1], oral 1·0 [0·1] litre kg⁻¹) were also similar after the two routes of dosing. The peak plasma concentration was reached 2·6 hours after oral dosing and the drug was completely bioavailable (1·09 [0·05]). On the basis of this single dose study, the administration of 50 mg fluconazole every eight hours to a 4 kg cat should produce average steady state plasma fluconazole concentrations of approximately 33 mg litre⁻¹.     

Pharmacokinetics of erythromycin after intravenous,intramuscular and oral administration to cats

The aim of this study was to characterise the pharmacokinetic properties of different formulations of erythromycin in cats. Erythromycin was administered as lactobionate (4 mg/kg intravenously (IV)), base (10 mg/kg, intramuscularly (IM)) and ethylsuccinate tablets or suspension (15 mg/kg orally (PO)). After IV administration, the major pharmacokinetic parameters were (mean ± SD): area under the curve (AUC)_(0–∞) 2.61 ± 1.52 μg h/mL; volume of distribution (V_z) 2.34 ± 1.76 L/kg; total body clearance (Cl_t) 2.10 ± 1.37 L/h kg; elimination half-life (t_½λ) 0.75 ± 0.09 h and mean residence time (MRT) 0.88 ± 0.13 h. After IM administration, the principal pharmacokinetic parameters were (mean ± DS): peak concentration (C_max), 3.54 ± 2.16 μg/mL; time of peak (T_max), 1.22 ± 0.67 h; t_½λ, 1.94 ± 0.21 h and MRT, 3.50 ± 0.82 h. The administration of erythromycin ethylsuccinate (tablets and suspension) did not result in measurable serum concentrations. After IM and IV administrations, erythromycin serum concentrations were above minimum inhibitory concentration (MIC)₉₀ = 0.5 μg/mL for 7 and 1.5 h, respectively. However, these results should be interpreted cautiously since tissue erythromycin concentrations have not been measured and can reach much higher concentrations than in blood, which may be associated with enhanced clinical efficacy.     

Pharmacokinetics of ciprofloxacin after single intravenous and repeat oral administration to cats

The pharmacokinetic properties of ciprofloxacin, a second-generation fluoroquinolone, were investigated in six cats after single intravenous and repeat oral administration at a dosage of 10 mg/kg b.i.d. Ciprofloxacin serum concentration was analyzed by microbiological assay using Klebsiella pneumoniae ATCC 10031 as microorganism test. Serum ciprofloxacin disposition was best fitted to a bicompartmental and a monocompartmental open models with first-order elimination after intravenous and oral dosing respectively. After intravenous administration, distribution was rapid (t(1/2(d)), 0.22 +/- 0.23 h) and wide as reflected by the steady-state volume of distribution of 3.85 +/- 1.34 L/kg. Furthermore, elimination was rapid with a plasma clearance of 0.64 +/- 0.28 L/h.kg and a t(1/2(el)) of 4.53 +/- 0.74 h. After repeat oral administration, absorption was rapid with a half-life of 0.23 +/- 0.22 h and T(max) of 1.30 +/- 0.67 h. However bioavailability was low (33 +/- 12%), the peak plasma concentration at steady-state was 1.26 +/- 0.67 microg/mL. Drug accumulation was not significant after seven oral administrations. When efficacy predictors were estimated ciprofloxacin showed a good profile against gram-negative bacteria when administered either intravenously or orally, although its efficacy against gram-positive microorganisms is lower.     

Pharmacokinetics of marbofloxacin after single intravenous and repeat oral administration to cats

The pharmacokinetic properties of marbofloxacin, a third generation fluoroquinolone, were investigated in six cats after single intravenous (IV) and repeat oral (PO) administration at a daily dose of 2 mg/kg. Marbofloxacin serum concentration was analysed by microbiological assay using Klebsiella pneumoniae ATCC 10031 as micro-organism test. Serum marbofloxacin disposition was best described by bicompartmental and mono-compartmental open models with first-order elimination after IV and oral dosing respectively. After IV administration, distribution was rapid (T(1/2(d)) 0.23+/-0.24 h) and wide, as reflected by the steady-state volume of distribution of 1.01+/-0.15 L/kg. Elimination from the body was slow with a body clearance of 0.09+/-0.02 L/h kg and a T(1/2) of 7.98+/-0.57 h. After repeat oral administration, absorption half-life was 0.86+/-1.59 h and T(max) of 1.94+/-2.11 h. Bioavailability was almost complete (99+/-29%) with a peak plasma concentration at the steady-state of 1.97+/-0.61 mug/mL. Drug accumulation was not significant after six oral administrations. Calculation of efficacy predictors showed that marbofloxacin has good therapeutic profile against Gram-negative and Gram-positive bacteria with a MIC(50) value <0.25 microg/mL.     

Pharmacokinetics of levofloxacin after single intravenous and repeat oral administration to cats

The pharmacokinetic properties of the fluoroquinolone levofloxacin, were investigated in five cats after single intravenous and repeat oral administration at a daily dose of 10 mg/kg. Levofloxacin serum concentration was analyzed by microbiological assay using Klebsiella pneumoniae ATCC 10031 as test microorganism. Serum levofloxacin disposition after intravenous and oral dosing was best fitted to a bicompartmental and a monocompartmental open models with first-order elimination, respectively. After intravenous administration, distribution was rapid (t(1/2(d)) 0.26 +/- 0.18 h) and wide as reflected by the steady-state volume of distribution of 1.75 +/- 0.42 L/kg. Drug elimination was slow with a total body clearance of 0.14 +/- 0.04 L/h.kg and a t(1/2) for this process of 9.31 +/- 1.63 h. The mean residence time was of 12.99 +/- 2.12 h. After repeat oral administration, absorption half-life was of 0.18 +/- 0.12 h and Tmax of 1.62 +/- 0.84 h. The bioavailability was high (86.27 +/- 43.73%) with a peak plasma concentration at the steady state of 4.70 +/- 0.91 microg/mL. Drug accumulation was not significant after four oral administrations. Estimated efficacy predictors for levofloxacin after either intravenous or oral administration indicate a good profile against bacteria with a MIC value below of 0.5 microg/mL. However, for microorganisms with MIC values of 1 microg/mL it would be efficacious only when administered intravenously.     

Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs

OBJECTIVE: To determine the pharmacokinetics of carvedilol administered IV and orally and determine the dose of carvedilol required to maintain plasma concentrations associated with anticipated therapeutic efficacy when administered orally to dogs. ANIMALS: 8 healthy dogs. PROCEDURES: Blood samples were collected for 24 hours after single doses of carvedilol were administered IV (175 microg/kg) or PO (1.5 mg/kg) by use of a crossover nonrandomized design. Carvedilol concentrations were detected in plasma by use of high-performance liquid chromatography. Plasma drug concentration versus time curves were subjected to noncompartmental pharmacokinetic analysis. RESULTS: The median peak concentration (extrapolated) of carvedilol after IV administration was 476 ng/mL (range, 203 to 1,920 ng/mL), elimination half-life (t(1/2)) was 282 minutes (range, 19 to 1,021 minutes), and mean residence time (MRT) was 360 minutes (range, 19 to 819 minutes). Volume of distribution at steady state was 2.0 L/kg (range, 0.7 to 4.3 L/kg). After oral administration of carvedilol, the median peak concentration was 24 microg/mL (range, 9 to 173 microg/mL), time to maximum concentration was 90 minutes (range, 60 to 180 minutes), t(1/2) was 82 minutes (range, 64 to 138 minutes), and MRT was 182 minutes (range, 112 to 254 minutes). Median bioavailability after oral administration of carvedilol was 2.1% (range, 0.4% to 54%). CONCLUSIONS AND CLINICAL RELEVANCE: Although results suggested a 3-hour dosing interval on the basis of MRT, pharmacodynamic studies investigating the duration of beta-adrenoreceptor blockade provide a more accurate basis for determining the dosing interval of carvedilol.     

Ronidazole pharmacokinetics after intravenous and oral immediate-release capsule administration in healthy cats

Ronidazole (RDZ) is an effective treatment for feline Tritrichomonas foetus infection, but has produced neurotoxicity in some cats. An understanding of the disposition of RDZ in cats is needed in order to make precise dosing recommendations. Single-dose pharmacokinetics of intravenous (IV) RDZ and immediate-release RDZ capsules were evaluated. A single dose of IV RDZ (mean 9.2mg/kg) and a 95mg immediate-release RDZ capsule (mean 28.2mg/kg) were administered to six healthy cats in a randomized crossover design. Plasma samples were collected for 48 h and assayed for RDZ using high pressure liquid chromatography (HPLC). Systemic absorption of oral RDZ was rapid and complete, with detection in the plasma of all cats by 10 min after dosing and a bioavailability of 99.64 (±16.54)%. The clearance of RDZ following IV administration was 0.82 (±0.07) ml/kg/min. The terminal half-life was 9.80 (±0.35) and 10.50 (±0.82) h after IV and oral administration, respectively, with drug detectable in all cats 48h after both administrations. The high oral bioavailability of RDZ and slow elimination may predispose cats to neurotoxicity with twice-daily administration. Less frequent administration should be considered for further study of effective treatment of T foetus-infected cats.     

Pharmacokinetics of gamithromycin after intravenous and subcutaneous administration in pigs

The aim of this study was to investigate the pharmacokinetic properties of gamithromycin in pigs after an intravenous (i.v.) or subcutaneous (s.c.) bolus injection of 6 mg/kg body weight. The plasma concentrations of gamithromycin were determined using a validated high-performance liquid chromatography–tandem mass spectrometry method, and the pharmacokinetics were noncompartmentally analysed.     

Pharmacokinetics of intravenous and oral methimazole following single-and multiple-dose administration in normal cats

The pharmacokinetics of methimazole (MMI) administered intravenously and orally were determined in six adult domestic shorthaired cats. There was no significant difference between mean serum MMI concentrations after oral and i.v. administration by 30 min post-MMI administration, indicating relatively rapid and complete absorption of the drug. The bioavailability of MMI ranged from 27% to 100% (mean = 81.1 +/- 11.4%). The mean serum elimination half-life was 6.6 +/- 2.0 h, with a wide range of values (1.9 h to 15.1 h). After repeat i.v. administration of MMI following 2 weeks of oral administration of the drug, no significant difference was found between mean serum concentrations after single-dose and multiple-dose administration. No significant change in serum elimination half-life or total body clearance was found after multiple-dose administration of MMI. Two cats with the longest half-lives (9.9 h and 15.1 h), however, did exhibit markedly shorter t1/2 values (3.5 h and 3.3 h, respectively) after multiple-dose administration. Values for central and steady state volumes of distribution also decreased after multiple-dose administration, possibly indicating saturation of thyroid uptake of MMI with chronic administration. These results indicate that MMI has good oral bioavailability and has a longer mean serum elimination half-life than propylthiouracil, the other anti-thyroid drug that has been evaluated in cats. Although no significant change in mean values occurred after multiple-dose administration of MMI, drug-induced acceleration of metabolism may occur in some cats after long-term MMI administration.     

Pharmacokinetics of acetazolimide after intravenous and oral administration in horses

OBJECTIVE: To determine the pharmacokinetics of acetazolamide administered IV and orally to horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Horses received 2 doses of acetazolamide (4 mg/kg of body weight, IV; 8 mg/kg, PO), and blood samples were collected at regular intervals before and after administration. Samples were assayed for acetazolamide concentration by high-performance liquid chromatography, and concentration-time data were analyzed. RESULTS: After IV administration of acetazolamide, data analysis revealed a median mean residence time of 1.71 +/- 0.90 hours and median total body clearance of 263 +/- 38 ml/kg/h. Median steady-state volume of distribution was 433 +/- 218 ml/kg. After oral administration, mean peak plasma concentration was 1.90 +/- 1.09 microg/ml. Mean time to peak plasma concentration was 1.61 +/- 1.24 hours. Median oral bioavailability was 25 +/- 6%. CONCLUSIONS AND CLINICAL RELEVANCE: Oral pharmacokinetic disposition of acetazolamide in horses was characterized by rapid absorption, low bioavailability, and slower elimination than observed initially after IV administration. Pharmacokinetic data generated by this study should facilitate estimation of appropriate dosages for acetazolamide use in horses with hyperkalemic periodic paralysis.     

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration

OBJECTIVE: To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. ANIMALS: 7 sexually intact, female, mixed-breed dogs. PROCEDURE: A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. RESULTS: PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.     

Pharmacokinetics after intravenous and oral administration of enrofloxacin in sheep

OBJECTIVE: To compare pharmacokinetics of enrofloxacin administered IV and in various oral preparations to ewes. ANIMALS: 5 mature Katahdin ewes weighing 42 to 50 kg. PROCEDURE: Ewes received 4 single-dose treatments of enrofloxacin in a nonrandomized crossover design followed by a multiple-dose oral regimen. Single-dose treatments consisted of an IV bolus of enrofloxacin (5 mg/kg), an oral drench (10 mg/kg) made from crushed enrofloxacin tablets, oral administration in feed (10 mg/kg; mixture of crushed enrofloxacin tablets and grain), and another type of oral administration in feed (10 mg/kg; mixture of enrofloxacin solution and grain). The multiple-dose regimen consisted of feeding a mixture of enrofloxacin solution and grain (10 mg/kg, q 24 h, for 7 days). Plasma concentrations of enrofloxacin and ciprofloxacin were measured by use of high-performance liquid chromatography. RESULTS: Harmonic mean half-life for oral administration was 14.80, 10.80, and 13.07 hours, respectively, for the oral drench, crushed tablets in grain, and enrofloxacin solution in grain. Oral bioavailability for the oral drench, crushed tablets in grain, and enrofloxacin in grain was 4789, 98.07, and 94.60%, respectively, and median maximum concentration (Cmax) was 1.61, 2.69, and 2.26 microg/ml, respectively. Median Cmax of the multiple-dose regimen was 2.99 microg/ml. CONCLUSIONS AND CLINICAL RELEVANCE: Enrofloxacin administered orally to sheep has a prolonged half-life and high oral bioavailability. Oral administration at 10 mg/kg, q 24 h, was sufficient to achieve a plasma concentration of 8 to 10 times the minimum inhibitory concentration (MIC) of any microorganism with an MIC < or = 0.29 microg/ml.     

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 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.