C. M. Cárceles

Pharmacokinetic–pharmacodynamic integration of orbifloxacin in rabbits after intravenous, subcutaneous and intramuscular administration

The single-dose disposition kinetics of orbifloxacin were determined in clinically normal rabbits (n=6) after intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration of 5 mg/kg bodyweight. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of orbifloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The concentration-time data were analysed by compartmental and noncompartmental kinetic methods. Steady-state volume of distribution (V(ss)) and total body clearance (Cl) of orbifloxacin after i.v. administration were estimated to be 1.71+/-0.38 L/kg and 0.91+/-0.20 L/h x kg, respectively. Following s.c. and i.m. administration orbifloxacin achieved maximum plasma concentrations of 2.95+/-0.82 and 3.24+/-1.33 mg/L at 0.67+/-0.20 and 0.65+/-0.12 h, respectively. The absolute bio-availabilities after s.c. and i.m. routes were 110.67+/-11.02% and 109.87+/-8.36%, respectively. Orbifloxacin showed a favourable pharmacokinetic profile in rabbits. However, on account of the low AUC/MIC and C(max)/MIC indices obtained, its use by i.m. and s.c. routes against the S. aureus strains assayed in this study cannot be recommended given the risk of selection of resistant populations.

Pharmacokinetics of amoxicillin/ciavulanic acid combination and of both drugs alone after intravenous administration to goats

The pharmacokinetic behaviour of an amoxicillin/clavulanic acid combination (25 mg kg-1), and both drugs alone (amoxicillin 20 mg kg-1), clavulanic acid 5 mg kg-1), was studied after intravenous (i.v.) administration of single doses of 10 goats. The objective was to determine whether there were differences in the plasma kinetics of these drugs when administered in combination or alone. The plasma concentration-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. The disposition curves for both drugs alone and in combination were best described by a biexponential equation (two-compartment open model). The elimination half-lives of amoxicillin were 1.05 +/- 0.09 h alone and 1.13 +/- 0.19 h in combination, and those of clavulanic acid were 0.87 +/- 0.07 h and 0.85 +/- 0.09 h, respectively. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two treatments. Body clearances of amoxicillin were 0.12 +/- 0.01 l h-1.kg alone and 0.11 +/- 0.01 l h-1.kg in combination, and of clavulanic acid were 0.12 +/- 0.02 l h-1.kg alone and 0.12 +/- 0.01 l h-1.kg in combination with amoxicillin. The half-lives and body clearances of amoxicillin and clavulanic acid did not differ significantly when administered alone and in combination. It was concluded that the i.v. administration of amoxicillin and clavulanic acid as a combination product did not alter the disposition kinetics of either drug.

Pharmacokinetics of danofloxacin in horses after intravenous, intramuscular and intragastric administration.

REASONS FOR PERFORMING STUDY Danofloxacin is a fluoroquinolone developed for veterinary medicine showing an excellent activity. However, danofloxacin pharmacokinetics profile have not been studied in horses previously. OBJECTIVE To study the pharmacokinetics following i.v., i.m. and intragastric (i.g.) administration of 1.25 mg/kg bwt danofloxacin to 6 healthy horses. METHODS A cross-over design was used in 3 phases (2 x 2 x 2), with 2 washout periods of 15 days (n = 6). Danofloxacin (18%) was administered by i.v. and i.m. routes at single doses of 1.25 mg/kg bwt. For i.g. administration an oral solution was prepared and administered via nasogastric tube. Danofloxacin concentrations were determined by HPLC assay with fluorescence detection. Tolerability at the the site of i.m. injection was monitored by creatine kinase (CK) activity. RESULTS Danofloxacin plasma concentration vs. time data after i.v. and i.g. administration could best be described by a 2-compartment open model. The disposition of i.m. administered danofloxacin was best described by a one-compartment model. The terminal half-lives for i.v., i.m. and i.g. routes were 6.31, 5.36 and 4.74 h, respectively. Clearance value after i.v. dosing was 0.34 l/kg bwt/h. After i.m. administration, absolute bioavailability was mean +/- s.d. 88.48 +/- 11.10% and Cmax was 0.35 +/- 0.05 mg/l. After i.g. administration, absolute bioavailability was 22.36 +/- 6.84% and Cmax 0.21 +/- 0.07 mg/l. CK activity following i.m. dosing increased 3-fold over pre-injection levels 12 h after dosing and subsequently approached (but did not reach) normal values at 72 h post dose. CONCLUSIONS Systemic danofloxacin exposure achieved in horses following i.m. administration was consistent with the predicted blood levels needed for a positive therapeutic outcome for many equine infections. Conversely, danofloxacin utility by the i.g. route was limited by low bioavailability. Tolerability associated with i.m. administration was high. POTENTIAL RELEVANCE Pharmacokinetics, blood levels and good tolerability of i.v. and i.m. administration of danofloxacin in horses indicates that it is likely to be effective for treating sensitive bacterial infections.

Pharmacokinetics of marbofloxacin in rabbit after intravenous, intramuscular, and subcutaneous administration.

The disposition kinetics of marbofloxacin, a fluoroquinolone antibiotic, after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration was determined in rabbits at a single dose of 2 mg/kg. Plasma concentrations of marbofloxacin were determined by high performance liquid chromatography with fluorescence detection. The concentration-time data were analysed by compartmental and non-compartmental pharmacokinetic methods. Steady-state volume of distribution (V(ss)) and clearance (Cl) of marbofloxacin after i.v. administration were 1.99±0.27 L/kg and 0.42±0.04 L/h kg, respectively. Following i.m. and s.c. administration marbofloxacin achieved maximum plasma concentrations of 2.04±0.32 and 1.64±0.15 mg/L at 0.33±0.16 and 0.50±0.18 h, respectively. The absolute bioavailabilities after i.m. and s.c. routes were 123.30±17.64% and 114.81±12.11%, respectively. From these data (kinetic parameters and absence of adverse reactions) marbofloxacin is likely to be effective in rabbits.

Pharmacokinetics of danofloxacin after single dose intravenous, intramuscular and subcutaneous administration to loggerhead turtles Caretta caretta

The single-dose disposition kinetics of the antibiotic danofloxacin were determined in clinically normal loggerhead turtles (n = 6) after intravenous (IV), subcutaneous (SC) and intramuscular (IM) administration of 6 mg kg(-1) bodyweight. Danofloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. The concentration-time data were analyzed by non-compartmental kinetic methods. Steady-state volume of distribution, and total body clearance of danofloxacin after IV administration were estimated to be 1.02 +/- 0.17 1 kg(-1) and 0.11 +/- 0.01 1 h(-1) kg(-1), respectively. Following IM and SC administration, danofloxacin achieved maximum plasma concentrations of 10.25 +/- 4.59 and 10.35 +/- 4.45 mg l(-1) at 1.20 +/- 0.52 and 1.46 +/- 0.48 h, respectively. The absolute bioavailabilities after SC and IM routes were 98.72 +/- 11.73 and 104.81 +/- 14.97%, respectively. Danofloxacin shows a favourable pharmacokinetic profile in loggerhead turtles reflected by parameters such as a long half-life and a high bioavailability following a single dose of 6 mg kg(-1) by IM and SC routes; thus, it is likely that this treatment will be effective in loggerhead turtles with bacterial infections.

Pharmacokinetics of amoxicillin‐clavulanic acid combination after intravenous and intramuscular administration to turkeys and chickens

The pharmacokinetic behaviour of amoxicillin/clavulanic acid (4:1) combination was studied after intravenous and intramuscular administration of single doses (25 mg/kg body weight) to 15 turkeys and 15 chickens. The objective was to determine whether there are differences between turkeys and chickens in the disposition kinetics of amoxicillin and clavulanic acid. The plasma concentrations-time data were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs after intravenous administration were best described by a two-compartment open model in turkeys and chickens. The apparent volumes of distribution of amoxicillin and clavulanic acid were similar in the two species. The body clearances of amoxicillin and clavulanic acid in turkeys were significantly slower than in chickens. The elimination half-life of amoxicillin was similar in turkeys (1.12 +/-0.09 h) and chickens (1.03 +/-0.11 h) after intravenous administration, but that of clavulanic acid differed significantly (P<0.05) between turkeys (1.12 +/-0.03 h) and chickens (0.98 +/- 0.05 h). After intramuscular administration both drugs had a significantly longer half-life (P<0.05) in turkeys and chickens than that after the intravenous treatment. The bioavailability after the intramuscular injection was high and similar with both drugs, but higher values were obtained for chickens than turkeys.

Pharmacokinetics of marbofloxacin after a single oral dose to loggerhead sea turtles (Caretta caretta).

The single-dose disposition kinetics of marbofloxacin (MBX) were determined in clinically healthy loggerhead sea turtles (n=5) after oral (PO) administration of 2 mg kg(-1) bodyweight. Marbofloxacin plasma concentrations were determined by DAD-HPLC (LOD/LOQ 0.015/0.05 microg ml(-1)). Data were subjected to non-compartmental analysis. Following PO administration, marbofloxacin achieved maximum plasma concentrations of 11.66+/-2.53 mg L(-1) at 15.00+/-3.00 h. The absence of general adverse reactions in the turtles of the study, and the favourable pharmacokinetic properties (long half-life and high maximum plasma concentration) of MBX administered PO at the single-dose of 2 mg kg(-1) suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.

PHARMACOKINETICS OF AMOXICILLIN/CLAVULANIC ACID COMBINATION AFTER INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION TO PIGEONS

The pharmacokinetics of amoxicillin/clavulanic acid (4:1) combination were studied after intravenous and intramuscular administration of single doses (25 mg kg(-1) bodyweight) to 50 pigeons. The plasma concentrations-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. The disposition curves for both drugs after intravenous administration were best described by a two-compartment open model. The apparent volumes of distribution of amoxicillin and clavulanic acid were 1.77 litres kg(-1) and 1.30 litres kg(-1) respectively. The body clearances of amoxicillin and clavulanic acid were not significantly different. The elimination half-lives of amoxicillin after intravenous and intramuscular administration were 1.22 (0.09) hour and 1.52 (0.09) hour respectively, and those of clavulanic acid were 1.15 (0.08) hour and 1.49 (0.08) hour. After intramuscular administration both drugs had a significantly longer half-life (P<0.05) than that after the intravenous treatment. The bioavailability after the intramuscular injection was high and similar for both drugs (75.98 per cent for amoxicillin and 74.61 per cent for clavulanic acid). The mean peak plasma concentration of clavulanic acid (0.29 hour) was reached earlier than amoxicillin (0.38 hour) and peak concentrations were proportional to the dose of both products administered (5.81 mg litre(-1) of amoxicillin and 1.89 mg litre(-1) of clavulanic acid). From a single administration it is proposed that an intramuscular dosage regimen of 105 mg kg(-1) of the combination (84 mg kg(-1) of amoxicillin and 21 mg kg(-1) of clavulanic acid) every 12 hours will achieve minimum concentrations > or =0.5 mg litre(-1) (minimum inhibitory concentration of most susceptible pathogens).

Pharmacokinetics after intravenous, intramuscular and subcutaneous administration of moxifloxacin in sheep.

The disposition kinetics of moxifloxacin, a fluoroquinolone antibiotic, after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration was determined in sheep at a single dose of 5mg/kg. The concentration-time data were analysed by compartmental (after IV dose) and non-compartmental (after IV, IM and SC administration) pharmacokinetic methods. Plasma concentrations of moxifloxacin were determined by high performance liquid chromatography with fluorescence detection. Steady-state volume of distribution (V(ss)) and clearance (Cl) of moxifloxacin after IV administration were 2.03+/-0.36L/kg and 0.39+/-0.04L/hkg, respectively. Following IM and SC administration, moxifloxacin achieved maximum plasma concentration of 1.66+/-0.62mg/L and 0.90+/-0.19mg/L at 2.25+/-0.88h and 3.25+/-1.17h, respectively. The absolute bioavailabilities after IM and SC routes were 96.12+/-32.70% and 102.20+/-23.76%, respectively. From these data (kinetic parameters and absence of adverse reactions) moxifloxacin may be a potentially useful antibiotic in sheep.

SOME PHARMACOKINETIC PARAMETERS OF AMPICILLIN/SULBACTAM COMBINATION AFTER INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION TO GOATS

Some pharmacokinetic parameters of an ampicillin/sulbactam (2:1) combination were studied in six goats, after intravenous and intramuscular injection at a single dosage of 20 mg/kg bodyweight (13.33 mg/kg of sodium ampicillin and 6.67 mg/kg of sodium sulbactam). The drugs were distributed according to an open two-compartment model. The apparent volumes of distribution calculated by the area method of ampicillin and sulbactam were 0.34 +/- 0.04 l/kg and 0.45 +/- 0.15 l/kg, respectively, and the total body clearances were 0.72 +/- 0.11 and 0.38 +/- 0.07 l/kg.h. The half-lives of ampicillin after intravenous and intramuscular administration were 0.32 +/- 0.04 h and 0.71 +/- 0.14 h, respectively. For sulbactam the half-lives were 0.79 +/- 0.18 h and 1.13 +/- 0.21 h after administration by the same routes. The bioavailability after intramuscular injection was high and similar for both drugs (98.29% for ampicillin and 101.84% for sulbactam). The mean peak plasma levels of ampicillin (0.43 +/- 0.27 h) and sulbactam (0.34 +/- 0.14 h) were reached at a similar time, and peak concentrations were also similar and non-proportional to the dose of the products administered (11.02 +/- 3.11 mg/l of ampicillin and 9.5 +/- 0.98 mg/l of sulbactam).