Pharmacokinetics and milk penetration of ibafloxacin after intravenous administration to lactating goats

The pharmacokinetic behavior of ibafloxacin was studied after intravenous administration of a single dose of 15 mg/kg to 6 healthy lactating goats. Plasma concentrations of ibafloxacin were determined by high-performance liquid chromatography with fluorescence detection. The data for concentration versus time could best be described by a 2-compartment model. The mean plasma ibafloxacin clearance (and standard error) was 1.05 (0.10) L/h x kg. The mean steady-state volume of distribution was 1.65 (0.42) L/kg. The mean elimination half-life was 3.76 (0.30) h. Ibafloxacin penetration from the blood to the milk was poor. The ratio between the areas under the concentration-time curve of milk and plasma was 0.20 (0.01), indicating scant penetration of ibafloxacin into the milk.     

Pharmacokinetics and milk penetration of moxifloxacin after intravenous and subcutaneous administration to lactating goats

The pharmacokinetics of moxifloxacin was studied following intravenous (IV) and subcutaneous (SC) administration of 5 mg/kg to healthy lactating goats (n = 6). Moxifloxacin concentrations were determined by high performance liquid chromatography assay with fluorescence detection. The moxifloxacin plasma concentration versus time data after IV administration could best be described by a two compartment open model. The disposition of SC administered moxifloxacin was best described by a one-compartment model. The plasma moxifloxacin clearance (Cl) for the IV route was 0.43 +/- 0.02 L/kg (mean +/- SE). The steady-state volume of distribution (Vss) was 0.79 +/- 0.08 L/kg. The terminal half-life (t1/2lambdaz) was 1.94 +/- 0.41 and 2.98 +/- 0.48 h after IV and SC administration, respectively. The absolute bioavailability was 96.87 +/- 10.27% after SC administration. Moxifloxacin penetration from blood to milk was quick for both routes of administration and the high AUCmilk/AUCplasma and Cmax-milk/Cmax-plasma ratios reached indicated a wide penetration of moxifloxacin into the milk. From these data, it appears that a 5 mg/kg SC dose of moxifloxacin would be effective in lactating goats against bacterial isolates with MIC < or = 0.20 microg/mL in plasma and MIC < or = 0.40 microg/mL in milk.     

Pharmacokinetics and milk penetration of difloxacin after intravenous, subcutaneous and intramuscular administration to lactating goats

The single-dose disposition kinetics of difloxacin were determined in clinically normal lactating goats (n = 6) after intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration of 5 mg/kg. Difloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. 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 difloxacin after i.v. administration were estimated to be 1.16 +/- 0.26 L/kg and 0.32 +/- 0.05 L/h x kg respectively. Following s.c. and i.m. administration difloxacin achieved maximum plasma concentrations of 1.33 +/- 0.25 and 1.97 +/- 0.40 mg/L at 3.37 +/- 0.36 and 1.79 +/- 1.14 h respectively. The absolute bioavailabilities after s.c. and i.m. routes were 90.16 +/- 11.99% and 106.79 +/- 13.95% respectively. Difloxacin penetration from the blood into the milk was extensive and rapid, and the drug was detected for 36 h after i.v. and s.c. dosing, and for 72 h after i.m. administration.     

Pharmacokinetics and milk penetration of moxifloxacin after intramuscular administration to lactating goats

The pharmacokinetics of moxifloxacin was studied following intramuscular administration of 5mg/kg to healthy lactating goats (n=6). Moxifloxacin concentrations were determined by high performance liquid chromatography assay with fluorescence detection. The moxifloxacin plasma concentration versus time data could best be described by a one-compartment model. The plasma moxifloxacin clearance (Cl) was mean standard deviation (+/-SD) 0.49+/-0.14 L/h kg. The apparent volume of distribution (V(z)) was 0.83+/-0.20 L/kg. The terminal half-life (t(1/2 lambda z)) was 1.31+/-0.64 h. Moxifloxacin penetration from blood to milk was rapid and the high AUC(milk)/AUC(plasma) and C(max-milk)/C(max-plasma) ratios reached indicated a good penetration of moxifloxacin into the milk.     

Pharmacokinetic interpretation of erythromycin and tylosin activity in serum after intravenous administration of a single dose to cows.

The distribution and elimination kinetics of erythromycin and tylosin, which are macrolide antibiotics, were studied in healthy cows. A single dose (12-5 mg/kg) of drug was administered as an intravenous bolus, and blood samples were collected at precisely timed intervals. The standard cylinder plate bioassay method using Sarcina lutea as test organism was employed to determine antibiotic activity in the serum. The results suggested that these drugs are distributed in at least two kinetically distinct body compartments. By use of established mathematical techniques, values were assigned to the individual rate constants controlling distribution between the central and peripheral compartments and to the rate constant controlling overall elimination (beta) of each drug from the body. The calculated overall tissue to serum drug level ratios (k12/k21) after apparent distribution equilibrium was attained were 2-28 and 2-05 for erythromycin and tylosin, respectively. The half-life (mean+/-SD) of erythromycin was 3-16 h+/-0-44, while that of tylosin was 1-62 h+/-0-17. The total body clearance (ml/kg/min) values were 2-88+/-0-47 for erythromycin and 7-8+/-2-95 for tylosin. Analogue computer simulated curves of the antibiotic levels in the central and tissue compartments as wel as an elimination curve were generated. The tissue level of erythromycin reached a peak of 43 per cent of the dose at 67 min. At 6 h, the percentages of the dose of erythromycin in the central and tissue compartments and eliminated were 6, 19 and 75, respectively. The peak level of tylosin in the tissue compartment (26-5 per cent of the dose) was present at 30 min. At 4 h, 1 and 5 per cent of the dose were contained in the central and peripheral compartments, respectively, while 94 per cent had been eliminated. This single dose study provides information which is essential for the design of a satisfactory dosage regimen.     

Non-linear pharmacokinetics of ofloxacin after a single intravenous bolus dose in pigs

The pharmacokinetics of ofloxacin (OFLX) was investigated after intravenous administration of 3, 10 and 30 mg/kg of body weight in pigs. Plasma OFLX concentration-time course collected from the highest dosage showed a convex decline, indicating a capacity-limited process in drug elimination (Michaelis-Menten elimination). Dose-normalized area under curve (AUC/Dose) and mean resident time (MRT) were dose-dependent, indicating a classical pattern of non-linear elimination pharmacokinetics. Based on simultaneous curve fitting from three doses, non-linear pharmacokinetic parameters were as follows: 0.87 mg/h/kg for maximum velocity, 2.20 microg/mL in Michaelis-Menten constant and 2.06 L/kg for apparent volume of distribution. Based on a model-independent analysis, the apparent volume of distribution at steady-state (Vdss) was dose-independent whereas total body clearance (CLtot) was dose-dependent, mainly contributed by renal clearance (CLr) with the regression line of CLtot=1.14xCLr+0.09 (r=0.92). The intercept of the regression line indicates non-renal clearance (CLnr), corresponding to the value of observed CLnr without dose-dependency. Because of a higher CLr compared with glomerular filtration rate (GFR) in spite of drug reabsorption, the CLr must contain the renal active tubular secretion. With increasing dosage, the level of saturation of tubular secretion of OFLX decreased the CLr, resulting in the decrease in CLtot. The plasma protein binding to OFLX was dose-independent: mean free fraction (fp)=0.73, with probably no influential effect on OFLX disposition. In conclusion, the degree of saturation in the renal active tubular secretion of OFLX could be a major causal factor in the alteration of CLr in an increasing dosage of OFLX. Accordingly, the alteration of CLr could directly induce the non-linear pharmacokinetics of OFLX in pigs, an important consideration in clinical therapeutics.     

Pharmacokinetics of erythromycin in nonlactating and lactating goats after intravenous and intramuscular administration

The objectives of this work were to compare the pharmacokinetics of erythromycin administered by the intramuscular (i.m.) and intravenous (i.v.) routes between nonlactating and lactating goats and to determine the passage of the drug from blood into milk. Six nonpregnant, nonlactating and six lactating goats received erythromycin by the i.m. (15 mg/kg) and the i.v. (10 mg/kg) routes of administration. Milk and blood samples were collected at predetermined times. Erythromycin concentrations were determined by microbiological assay. Results are reported as mean +/- SD. Comparison of the pharmacokinetic profiles between nonlactating and lactating animals after i.v. administration indicated that significant differences were found in the mean body clearance (8.38 +/- 1.45 vs. 3.77 +/- 0.83 mL/kg x h respectively), mean residence time (0.96 +/- 0.20 vs. 3.18 +/- 1.32 h respectively), area under curve from 0 to 12 h (AUC(0-12)) (1.22 +/- 0.22 vs. 2.76 +/- 0.58 microg x h/mL respectively) and elimination half-life (1.41 +/- 1.20 vs. 3.32 +/- 1.34 h); however, only AUC(0-12) showed significant differences after the i.m. administration. Passage of erythromycin in milk was high (peak milk concentration/peak serum concentration, 2.06 +/- 0.36 and AUC(0-12milk)/AUC(0-12serum),6.9 +/- 1.05 and 2.37 +/- 0.61 after i.v. and i.m. administrations respectively). We, therefore, conclude that lactation affects erythromycin pharmacokinetics in goats.     

Enantiomeric disposition of ketorolac in goats following administration of a single intravenous and oral dose

The purpose of this study was to investigate the stereospecific pharmacokinetics of ketorolac (KT) in goats following a single 2 mg/kg intravenous (i.v.) dose and a single 6 mg/kg oral dose. A stereoselective high pressure liquid chromatography assay was used to quantify ketorolac plasma concentrations. Pharmacokinetic parameters for both stereoisomers were estimated by model independent methods. Following an i.v. dose, the plasma concentration profiles for the stereoisomers were similar with half-lives of 1.05 ± 0.62 h for R -KT and 1.05 ± 0.61 h for S -KT. Clearance values for R - and S -KT after an i.v. dose were 0.53 ± 0.23 and 0.54 ± 0.23 L·h/kg, respectively. Following an oral dose, the terminal half-lives were longer with values of 34.08 ± 11.81 and 33.97 ± 12.19 h for R -KT and S- KT, respectively. The average bioavailability was 133 ± 23% for R -KT and S -KT, respectively. The longer half-lives and high apparent bioavailability after oral dosing are suggestive of a slow absorption process in the gastrointestinal tract and recycling. The results indicate that interconversion of the stereoisomers of ketorolac is absent in goats. However, studies with individual isomers are needed before any conclusion can be drawn about the lack of bioinversion.     

Pharmacokinetic parameters of ceftriaxone after single intravenous and intramuscular administration in camels (Camelus Dromedarius)

The purpose of this study was to investigate the plasma disposition kinetics of ceftriaxone in female camels (n=5) following a single intravenous (i.v.) bolus or intramuscular (i.m.) injections at a dosage of 10mg kg(-1) body weight in all animals. A crossover design was carried out in two phases separated by 15 days. Jugular blood samples were collected serially for 48h and the plasma was analysed by high-performance liquid chromatography (HPLC). Following single i.v. injections the plasma concentration time curves of ceftriaxone were best fitted to a two-compartment model. The drug was rapidly distributed with half-life of distribution t(1/2alpha) of 0.24+/-0.01h and moderately eliminated with elimination rate constant and elimination half-life of 0.27+/-0.13h(-1) and 2.57+/-0.52h, respectively. The volume of distribution at steady state (V(dss)) was 0.32+/-0.01lkg(-1) and the total body clearance (Cl(tot)) was 0.11+/-0.01lkg(-1)h(-1), respectively. Following i.m. administration, the mean T(max), C(max), t(1/2el) and AUC values for plasma data were 1.03+/-0.23h, 21.54+/-2.61microg ml(-1), 1.76+/-0.03h and 85.82+/-11.21microg ml(-1)h(-1), respectively. The i.m. bioavailability was 93.42+/-21.4% and the binding percentage of ceftriaxone to plasma protein was moderate, ranging from 33% to 42% with an average of 34.5%.     

Pharmacokinetics of gentamicin following single dose intravenous administration in normal and febrile goats

A pharmacokinetic study of gentamicin (5 mg/kg intravenous (i.v.)) was conducted first in cinically healthy female goats and then in the same goats after induction of fever by Escherichia coli endotoxin (0.2 μg/kg i.v.). Rectal temperature increased 1 to 1.5°C in febrile goats. Differences in the blood serum concentrations of gentamicin were not observed at any time between febrile and normal goats. The disposition kinetics of gentamicin were described by a biex-ponential expression C_P= Ae^-αt+ Be^-β. Median values for the half-lives of gentamicin were 103.6 min in normal and 136.0 min in febrile goats. The apparent volume of distribution (V_d) was 263.3 ml/kg in the febrile goats which was not different from that in the normal goats (240.6 ml/kg). The volume of the central compartment (V_c) was almost identical in normal and febrile goats. The body clearance (Cl_β) was observed to be 1.7 and 1.6 ml/min-kg in normal and febrile goats, respectively. Dosage regimens for gentamicin were calculated on the basis of median kinetic data.     

Pharmacokinetics of voriconazole after single dose intravenous and oral administration to alpacas

Voriconazole is a new antifungal drug that has shown effectiveness in treating serious fungal infections and has the potential for being used in large animal veterinary medicine. The objective of this study was to determine the plasma concentrations and pharmacokinetic parameters of voriconazole after single-dose intravenous (i.v.) and oral administration to alpacas. Four alpacas were treated with single 4 mg/kg i.v. and oral administrations of voriconazole. Plasma voriconazole concentrations were measured by a high-performance liquid chromatography method. The terminal half-lives following i.v. and oral administration were 8.01 ± 2.88 and 8.75 ± 4.31 h, respectively; observed maximum plasma concentrations were 5.93 ± 1.13 and 1.70 ± 2.71 μg/mL, respectively; and areas under the plasma concentration vs. time curve were 38.5 ± 11.1 and 9.48 ± 6.98 mg·h/L, respectively. The apparent systemic oral availability was low with a value of 22.7 ± 9.5%. The drug plasma concentrations remained above 0.1 μg/mL for at least 24 h after single i.v. dosing. The i.v. administration of 4 mg/kg/day voriconazole may be a safe and appropriate option for antifungal treatment of alpacas. Due to the low extent of absorption in alpacas, oral voriconazole doses of 20.4 to 33.9 mg/kg/day may be needed.     

Pharmacokinetics of cefonicid in lactating goats after intravenous,intramuscular and subcutaneous administration,and after a long-acting formulation for subcutaneous administration

The single-dose disposition kinetics of cefonicid were determined in clinically normal lactating goats (n = 6) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration of a conventional formulation, and after subcutaneous administration of a long-acting formulation (SC-LA). Cefonicid concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration–time data were analysed by noncompartmental pharmacokinetic methods. Steady-state volume of distribution (V_ss) and clearance (Cl) of cefonicid after IV administration were 0.14 ± 0.03 L/kg and 0.51 ± 0.07 L/h·kg, respectively. Following IM, SC and SC-LA administration, cefonicid achieved maximum plasma concentrations of 14.46 ± 0.82, 11.98 ± 1.92 and 17.17 ± 2.45 mg/L at 0.26 ± 0.13, 0.42 ± 0.13 and 0.83 ± 0.20 hr, respectively. The absolute bioavailabilities after IM, SC and SC-LA routes were 75.34 ± 11.28%, 71.03 ± 19.14% and 102.84 ± 15.155%, respectively. After cefonicid analysis from milk samples, no concentrations were found above LOQ at any sampling time. From these data, cefonicid administered at 20 mg/kg each 12 hr after SC-LA could be effective to treat bacterial infections in lactating animals not affected by mastitis problems.     

Pharmacokinetics,milk penetration and PK/PD analysis by Monte Carlo simulation of marbofloxacin,after intravenous and intramuscular administration to lactating goats

The main objectives of this study were (i) to evaluate the serum pharmacokinetic behaviour and milk penetration of marbofloxacin (MFX; 5 mg/kg), after intravenous (IV) and intramuscular (IM) administration in lactating goats and simulate a multidose regimen on steady‐state conditions, (ii) to determine the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of coagulase negative staphylococci (CNS) isolated from caprine mastitis in Córdoba, Argentina and (iii) to make a PK/PD analysis by Monte Carlo simulation from steady‐state pharmacokinetic parameters of MFX by IV and IM routes to evaluate the efficacy and risk of the emergence of resistance. The study was carried out with six healthy, female, adult Anglo Nubian lactating goats. Marbofloxacin was administered at 5 mg/kg bw by IV and IM route. Serum and milk concentrations of MFX were determined with HPLC/uv. From 106 regional strains of CNS isolated from caprine mastitis in herds from Córdoba, Argentina, MICs and MPCs were determined. MIC₉₀ and MPC₉₀ were 0.4 and 6.4 μg/ml, respectively. MIC and MPC‐based PK/PD analysis by Monte Carlo simulation indicates that IV and IM administration of MFX in lactating goats may not be adequate to recommend it as an empirical therapy against CNS, because the most exigent endpoints were not reached. Moreover, this dose regimen could increase the probability of selecting mutants and resulting in emergence of resistance. Based on the results of Monte Carlo simulation, the optimal dose of MFX to achieve an adequate antimicrobial efficacy should be 10 mg/kg, but it is important take into account that fluoroquinolones are substrates of efflux pumps, and this fact may determine that assumption of linear pharmacokinetics at high doses of MFX may be incorrect.     

Some pharmacokinetic parameters of ampicillin/sulbactam combination after intravenous and intramuscular administration to goats

Summary

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 1/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).     

Pharmacokinetics of azithromycin after intravenous and intramuscular administration to goats

Azithromycin is the first of a class of antimicrobial agents designated azalides. The aim of the present study was to investigate the disposition pharmacokinetics of azithromycin in goats and determine its bioavailability. A cross-over study was carried out in two phases separated by 30 days. Azithromycin was administered at a single dose of 20 mg/kg body weight by i.v. and i.m. routes. Plasma concentrations of azithromycin were determined by a modified agar diffusion bioassay. After a single i.v. dose plasma concentrations were best fitted to a three-compartment open model. A two-compartment open model with first-order absorption fitted best after i.m. administration. The values of the pharmacokinetic parameters after i.v. administration were: half-life 32.5 h, apparent volume of distribution at the steady-state 34.5 L/kg, clearance 0.85 L/kg. and mean residence time (MRT) 40.1 h. After i.m. administration half-life of 45.2 h, a MRT of 60.3 h, maximum plasma concentration 0.64 mg/L and a bioavalability 92.2% were obtained. The pharmacokinetic parameters of azithromycin after i.m. administration, principally its long half-life and high bioavailability, could provide an alternative to the oral route of administration in goats, although more studies are needed to establish a suitable pharmaceutical formulation, propose optimun dosage regimens, investigate clinical efficacy and study the tolerability of repeated doses.     

Pharmacokinetics of ketorolac after intravenous and oral single dose administration in dogs

The pharmacokinetics of ketorolac (Toradol), a human non-narcotic, nonsteroidal anti-inflammatory drug (NSAID) of the pyrrolo-pyrrole group, was studied in six mixed breed dogs of varying ages (1-5 years). The study was performed using a randomized crossover design, with each dog initially assigned to one of two groups (intravenous (i.v.) or oral (p.o.)). Each group of three dogs received either the injectable or oral formulation of ketorolac tromethamine at 0.5 mg/kg. Serial blood samples were collected before and over 96 h following treatment. Samples were analysed by reverse phase HPLC. Individual ketorolac plasma concentration-time curves were initially evaluated by computerized curve stripping techniques followed by nonlinear least squares regression. Following i.v. administration mean (+/- SD) pharmacokinetic parameters were: elimination half-life (t1/2 beta) = 4.55 h, plasma clearance (Clp) = 1.25 (1.13) mL/kg/min, and volume of distribution at steady state (Vss) = 0.33 (0.10) L/kg. Mean (+/- SD) p.o. pharmacokinetic values were: t1/2 beta = 4.07 h, time to reach maximum concentration (tmax) = 51.2 (40.6) min, and p.o. bioavailability (F) = 100.9 (46.7)%. These results suggest that the pharmacodisposition characteristics of a clinically effective 0.5 mg/kg i.v. or p.o. single dose of ketorolac tromethamine administered to dogs is fairly similar to that observed in humans.     

Serum and milk concentrations of apramycin in lactating cows, ewes and goats

A 20% solution of apramycin was administered intravenously (j.v.) and intramuscularly (i.m.) to lactating cows with clinically normal and acutely inflamed udders, to lactating ewes with normal or subclinically infected, inflamed udders and i.v. to lactating goats with normal udders. The i.v. disposition kinetics of apramycin was very similar in cows, ewes and goats. The elimination half-life was approximately 2 h and the steady-state volume of distribution was 1.26–1.45 L/kg. The absorption rate of the drug from the i.m. injection site was rapid, the i.m. bioavailability was 60–70% and the mean elimination half-life was 265 min in cows and 145.5 min in ewes. The binding percentage of apramycin to serum protein was low (< 22.5%). Concentrations of apramycin in milk produced by clinically normal mammary glands of cows, ewes and goats were consistently lower than in serum; the kinetic value AUC _milk/ AUC _serum was < 0.32. Drug penetration into the milk from the acutely inflamed quarters of cows was extensive; mastitis milk C _max values were more than tenfold greater than the C _max in normal milk. On the other hand, the drug had limited access to the milk produced by subclinically infected inflamed half-udders of ewes.     

Pharmacokinetic and tissue distribution study of oxytetracycline in rainbow trout following bolus intravenous administration

Oxytetracycline pharmacokinetics and tissue distribution were studied in rainbow trout following bolus i.v. administration at 5 mg/kg. The mean serum (log) drug concentration data were plotted against time (linear). The decay curve was described by a three-component exponential decay function and a three-compartment model. The t1/2 of rapid distribution was 0.9 h, the t1/2 of the slow distribution was 5.9 h and the t1/2 elimination was 81.5 h. Clearance was 25.4 ml/kg/h and Vd(area) 2988 ml/kg. Regression analysis of the serum levels for the three intervals, 0.5-2.0 h, 6.0-18.0 h, and 24-96 h, indicated that the rates of decay for each interval were 0.6151 h-1, 0.0564 h-1 and 0.0088 h-1 respectively. Rates of equilibration between tissues and serum were determined. Kidney equilibrated the fastest with t1/2 to equilibration of 1.1 h for H (anterior) kidney and 1.98 h for P (posterior) kidney. The highest drug levels were found in the liver and the lowest were in the brain.