Pharmacokinetics of spiramycin after intravenous, intramuscular and subcutaneous administration in lactating cows

Spiramycin is a macrolide antibiotic that is active against most of the microorganisms isolated from the milk of mastitic cows. This work investigated the disposition of spiramycin in plasma and milk after intravenous, intramuscular and subcutaneous administration. Twelve healthy cows were given a single injection of spiramycin at a dose of 30,000 IU/kg by each route. Plasma and milk were collected post injection. Spiramycin concentration in the plasma was determined by a high performance liquid chromatography method, and in the milk by a microbiological method. The mean residence time after intravenous administration was significantly longer (P less than 0.01) in the milk (20.7 +/- 2.7 h) than in plasma (4.0 +/- 1.6 h). An average milk-to-plasma ratio of 36.5 +/- 15 was calculated from the area concentration-time curves. Several pharmacokinetic parameters were examined to determine the bioequivalence of the two extravascular routes. The dose fraction adsorbed after intramuscular or subcutaneous administration was almost 100% and was bioequivalent for the extravascular routes, but the rates of absorption, the maximal concentrations and the time to obtain them differed significantly between the two routes. Spiramycin quantities excreted in milk did not differ between the two extravascular routes but the latter were not bioequivalent for maximal concentration in the milk. However, the two routes were bio-equivalent for the duration of time the milk concentration exceeded the minimal inhibitory concentration (MIC) of various pathogens causing infections in the mammary gland.(ABSTRACT TRUNCATED AT 250 WORDS)     

Depletion of florfenicol in lactating dairy cows after intramammary and subcutaneous administration

Eighteen Holstein dairy cows ranging in body weight from 500–700 kg and with an average milk yield of 37 ± 6 kg/day were used to investigate the depletion of florfenicol (FFL) in milk and plasma of dairy cows. Three groups of six were administered FFL: Group A, intramammary (IMM) infusion of ~2.5 mg FFL/kg BW at three consecutive milking intervals (total amount of ~7.5 mg/kg BW); Group B, one IMM infusion (20 mg/kg BW) into one quarter and Group C, one subcutaneous (SC) treatment (40 mg/kg BW). IMM infusions were into the right front quarter. Cows were milked daily at 06:00 and 18:00 h. The highest concentrations (C_max) and time to C_max (T_max) were: 1.6 ± 2.2 μg·FFL/mL milk at 22 h (Group A), 5.5 ± 3.6 μg·FFL/mL milk at 12 h (Group B), and 1.7 ± 0.4 μg·FFL/mL milk at 12 h (Group C). The half‐lives (t_1/2) were ~19, 5.5, and 60 h, for Groups A, B, and C, respectively. FFL was below the limit of detection (LOD) by 60 h in three Group B cows, but above the LOD at 72, 84, and 120 h in three cows. FFL was above the LOD in milk from Group C's cows for 432–588 h. Plasma values followed the same trends as milk. The results demonstrate that IMM‐infused FFL is bioavailable and below the LOD within 72–120 h. The concentration of FFL was detectable in both plasma and milk over the course of 2–3 weeks after SC administration. The absence of residue depletion data presents problems in determining safe levels of FFL residues in milk and edible tissues. The data presented here must not be construed as approval for extra‐label use in food animals.     

Elimination kinetics of ceftiofur hydrochloride after intramammary administration in lactating dairy cows

OBJECTIVE: To determine the elimination kinetics of ceftiofur hydrochloride in milk after intramammary administration in lactating dairy cows. DESIGN: Prospective study. ANIMALS: 5 lactating dairy cows. PROCEDURE: After collection of baseline milk samples, 300 mg (6 mL) of ceftiofur was infused into the left front and right rear mammary gland quarters of each cow. Approximately 12 hours later, an additional 300 mg of ceftiofur was administered into the same mammary gland quarters after milking. Milk samples were collected from each mammary gland quarter every 12 hours for 10 days. Concentrations of ceftiofur and its metabolites in each milk sample were determined to assess the rate of ceftiofur elimination. RESULTS: Although there were considerable variations among mammary gland quarters and individual cows, ceftiofur concentrations in milk from all treated mammary gland quarters were less than the tolerance (0.1 microg/mL) set by the FDA by 168 hours (7 days) after the last intramammary administration of ceftiofur. No drug concentrations were detected in milk samples beyond this period. Ceftiofur was not detected in any milk samples from nontreated mammary gland quarters throughout the study. CONCLUSIONS AND CLINICAL RELEVANCE: Ceftiofur administered by the intramammary route as an extra-label treatment for mastitis in dairy cows reaches concentrations in milk greater than the tolerance set by the FDA. Results indicated that milk from treated mammary gland quarters should be discarded for a minimum of 7 days after intramammary administration of ceftiofur. Elimination of ceftiofur may be correlated with milk production, and cows producing smaller volumes of milk may have prolonged withdrawal times.     

Pharmacokinetics of enrofloxacin after single intravenous, intramuscular and subcutaneous injections in lactating cows

Five Ayrshire cows were given enrofloxacin (5 mg/kg body weight) intravenously (i.v.), intramuscularly (i.m.) and subcutaneously (s.c). The antimicrobial activity was measured in milk and serum samples using the agar-diffusion technique. High-performance liquid chromatography (HPLC) assay was used to study the extent of metabolism of enrofloxacin to dprofloxacin. Analysis of the serum concentration-time data was based on statistical moment theory. Mean t _1/2β of antimicrobial activity in serum was 1.7, 5.9 and 5.6 h after i.v., i.m. and s.c. administration, respectively. Both i.m. and s.c. routes were associated with a marked flip-flop phenomenon. Based on HPLC analysis of serum samples, the half-lives of enrofloxacin and ciprofloxacin were approximately the same. A marked proportion of enrofloxacin was metabolized to ciprofloxacin. The enrofloxacin fraction bound in vitro to serum proteins was 36–45%. About 0.2% of the total enrofloxacin dose was found in milk during the first 24h and the amount transferred did not depend on the route of administration. Based on the HPLC data, enrofloxacin concentration in milk was parallel to that in serum, while ciprofloxacin was concentrated in milk. After i.v. injection, the peak concentration of enrofloxacin in milk was reached between 0.7 and 1.3 h but occurred much later for ciprofloxacin ( t _max 5–8 h). After i.m. and s.c. administration the concentration-time curves for both enrofloxacin and ciprofloxacin in milk were shallow and there were no obvious peaks.     

Determination of milk/plasma ratio and milk and plasma pharmacokinetics of amoxicillin after intramuscular administration in lactating cows

This study was conducted to determine the passage ratio of amoxicillin into milk and its pharmacokinetics in milk and plasma after intramuscular administration. Five healthy dairy cows (Holstein, weighing 450–500 kg, aged 2–4 years) were used in this study. They received single intramuscular amoxicillin at a dose of 14 mg/kg body weight. Blood and milk samples were collected prior to drug administration (0); after 15, 30, 45, 60, and 90 min; and 2, 3, 4, 6, 8, 10, and 12 hr after administration. The plasma and milk concentrations of amoxicillin were determined using high‐performance liquid chromatography with ultraviolet detection. The passage ratio of amoxicillin into milk and plasma was determined using both AUC‐based calculation and milk and plasma concentrations at sampling times; it was calculated 0.46 and 0.52, respectively. The terminal half‐life and mean residence time of amoxicillin were 6.05 and 8.60 hr in plasma and 2.62 and 5.35 hr in milk, respectively. The C_max2 levels of amoxicillin in plasma and milk were measured as 1,096 and 457 ng/ml, respectively. It was observed that amoxicillin exhibited a secondary peak in plasma and milk. This study was the first to report on the passage ratio of amoxicillin into milk in lactating cows.     

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.     

The pharmacokinetics of midazolam after intravenous,intramuscular, and rectal administration in healthy dogs

Intravenous benzodiazepines are utilized as first‐line drugs to treat prolonged epileptic seizures in dogs and alternative routes of administration are required when venous access is limited. This study compared the pharmacokinetics of midazolam after intravenous (IV), intramuscular (IM), and rectal (PR) administration. Six healthy dogs were administered 0.2 mg/kg midazolam IV, IM, or PR in a randomized, 3‐way crossover design with a 3‐day washout between study periods. Blood samples were collected at baseline and at predetermined intervals until 480 min after administration. Plasma midazolam concentrations were measured by high‐pressure liquid chromatography with UV detection. Rectal administration resulted in erratic systemic availability with undetectable to low plasma concentrations. Arithmetic mean values ± SD for midazolam peak plasma concentrations were 0.86 ± 0.36 μg/mL (C₀) and 0.20 ± 0.06 μg/mL (C_max), following IV and IM administration, respectively. Time to peak concentration (T_max) after IM administration was 7.8 ± 2.4 min with a bioavailability of 50 ± 16%. Findings suggest that IM midazolam might be useful in treating seizures in dogs when venous access is unavailable, but higher doses may be needed to account for intermediate bioavailability. Rectal administration is likely of limited efficacy for treating seizures in dogs.     

Pharmacodynamics and pharmacokinetics of flumequine in pigs after single intravenous and intramuscular administration

The pharmacokinetics and intramuscular (IM) bioavailability of flumequine (15 mgkg(-1)) were investigated in healthy pigs and the findings related to published minimal inhibitory concentrations (MICs) for susceptible bacteria of animal origin, and to experimentally determined MICs for susceptible strains of porcine origin. We found MICs for Escherichia coli, Salmonella spp., Pasteurella spp. and Bordetella spp. in the range 0.5 to >64 microg mL(-1) isolated from infected pigs in the Forli area of Italy; only the Pasteurella multocida strains were sensitive (MIC(90)=0.5 microg mL(-1)). After intravenous (IV) injection, flumequine was slowly distributed and eliminated (t(1/2lambda(1))1.40+/-0.16 h and t(1/2lambda(2))6.35+/-1.69 h). The distribution volume at steady state (V(dss)) was 752.59+/-84.03 mL kg(-1) and clearance (Cl(B)) was 237.19+/-17.88 mL kg(-1)h(-1). After IM administration, peak serum concentration (4.99+/-0.92 microg mL(-1)) was reached between the 2nd and the 3rd hour. The results on MIC of isolated bacteria, although only indicative, suggest that the efficacy of flumequine on Gram-negative bacteria may be impaired by the emergence of less sensitive or resistant strains.     

Ampicillin pharmacokinetics in swine following needle-free, intramuscular, and intravenous administration

A cross-over study design was used to determine the pharmacokinetics of ampicillin in swine. Each of eight pigs was subjected to all of the following three treatments: (1) intramuscular (i.m.) injection of 17.6 mg/kg of ampicillin trihydrate; (2) injection of a mean dose of 17.6 mg/kg of ampicillin trihydrate using a needle-free (NF) injection device; and (3) intravenous injection of 17.6 mg/kg of sodium ampicillin administered as a bolus. Ampicillin trihydrate administered by NF injection in this study was not statistically different from i.m. injection as measured by AUC(0-infinity), MRT, MAT, or Cmax. However, the 90% confidence limits about the difference in NF to i.m. mean Cmax and AUC(0-infinity) values, expressed relative to the i.m. treatment mean, exceeded the traditional bioequivalence limits of +/-20%. In part, failure to demonstrate bioequivalence was attributable to small study size and the large within-subject variability associated with this drug. Therefore the power of this study was not sufficient to definitively prove or disprove bioequivalence and additional studies to describe appropriate dosage regimens for ampicillin trihydrate when administered by NF injection to pigs are warranted.     

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.     

Clinical pharmacokinetics of norfloxacin-glycine acetate after intravenous and intramuscular administration to horses

The pharmacokinetic properties of norfloxacin-glycine acetate (NFLXGA) were determined in six horses following a single intravenous (i.v.) and intramuscular (i.m.) dose of 4 mgkg(-1) body weight. Following i.v. and i.m. administration, the plasma drug concentrations were best fitted by an open two-compartment model with a rapid distribution phase. After i.v. NFLXGA administration, the distribution (t(1/2alpha)) and elimination half-life (t(1/2beta)) were 0.42 (0.05) and 5.44 (1.36)h. The volume of distribution of NFLXGA at steady state (Vd(ss)) was 2.19 (0.53) Lkg(-1). After NFLXGA i.m. administration, the maximal absorption concentration (C(max)) was 0.44 (0.04) microgml(-1) at 0.86 (0.15)h (T(max)). The mean absorption (t(1/2ka)) and elimination half-life (t(1/2beta)) of NFLXGA were 0.27 (0.07) and 9.47 (2.24)h, respectively. The mean systemic bioavailability (F) following i.m. administration was 55 (12)%. The optimal dosage for each administration route was calculated from the pharmacokinetic data on the basis of the area under the inhibitory plasma concentration-time curve (AUIC) every 24h and was found to be 13.36 and 7.35 mgkg(-1) for i.m. and i.v. administration, respectively.     

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 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 bioavailability of carbetocin after intravenous and intramuscular administration in cows and gilts

The pharmacokinetics of carbetocin, which is used to control postpartum hemorrhage after giving birth, was studied in cows and gilts after a single intravenous (IV) or intramuscular (IM) injection. Blood samples from animals were assessed by oxytocin radioimmunoassay, and then the pharmacokinetic parameters were calculated using a noncompartmental model. For gilts, there was no significant difference between half-life (T_1/2λZ), mean residue time (MRT), and maximum concentration (C_max) between IM and IV administration. Conversely, the time to reach the C_max (T_max) and MRT were higher following administration of 350 μg/animal in cows via the IM administration compared with IV. The longest T_1/2λZ was 0.85 hr, indicating carbetocin was absorbed and eliminated rapidly in both animal species after administration. The T_max was similar between cows and gilts following IM administration. Moreover, the C_max after IM injection was about half that of IV administration in both animals. The bioavailability was more than 80% in cows, suggesting administration via the IM route is efficient. This is in agreement with the longer T_1/2λZ in cows after IM administration. However, the IV route is recommended for gilts due to a lower bioavailability (35%) and shorter T_1/2λZ after IM administration compared with IV.     

Combined pharmacokinetics of gentamicin in pony mares after a single intravenous and intramuscular administration

Healthy mature pony mares (n = 6) were given a single dose of gentamicin (5 mg/kg of body weight) IV or IM 8 days apart. Venous blood samples were collected at 0, 5, 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, 30, 36, 40, and 48 hours after IV injection of gentamicin, and at 10, 20, 30, and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, 24, and 30 hours after IM injection of gentamicin. Gentamicin serum concentration was determined by a liquid-phase radioimmunoassay. The combined data of IV and IM treatments were analyzed by a nonlinear least-square regression analysis program. The kinetic data were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the correlation of determination. The distribution phase half-life was 0.12 +/- 0.02 hour and postdistribution phase half-life was 1.82 +/- 0.22 hour. The volume of the central compartment was 115.8 +/- 6.0 ml/kg, volume of distribution at steady state was 188 +/- 9.9 ml/kg, and the total body clearance was 1.27 +/- 0.18 ml/min/kg. Intramuscular absorption was rapid with a half-life for absorption of 0.64 +/- 0.14 hour. The extent of absorption was 0.87 +/- 0.14. Kinetic calculations predicted that IM injections of 5 mg of gentamicin/kg every 8 hours would provide average steady-state serum concentrations of 7.0 micrograms/ml, with maximum and minimum steady-state concentrations of 16.8 and 1.1 micrograms/ml, respectively.     

Pharmacokinetics and renal clearance of oxytetracycline after intravenous and intramuscular administration to dairy cows

Following intravenous administration of an oxytetracycline-HC1 and an oxytetracycline-dihydrate formulation to dairy cows, no statistical difference could be found between the pharmacokinetic parameters, derived from the three-compartment model, of these preparations. Urinary recovery was continued for a period of 72 h following intravenous or intramuscular OTC administration. The recovery of OTC in the urine in the 72-h period was in the range of 73% to 96% of the available dose administered. The renal OTC clearance, the renal creatinine clearance, the urinary flow, and the interrelationships of these were determined on the basis of urine and plasma data. The mean OTC renal clearance ranged from 482 to 1050 ml/min and the creatinine clearance from 651 to 1304 ml/min. The OTC and creatinine clearances were significantly correlated to the urine flow up to 30 ml/min. The total body clearance and renal clearance values were of the same order of magnitude, and along with the urine recovery data they provided evidence of predominantly renal route of OTC elimination in dairy cows. The renal OTC elimination is the net result of mainly glomerular filtration, partly tubular secretion, minus reabsorption in the urogenital tract.     

Pharmacokinetics and renal clearance of oxytetracycline after intravenous and intramuscular administration to dairy cows

Summary

Following intravenous administration of an oxytetracycline‐HC 1 and an oxytetracycline‐dihydrate formulation to dairy cows, no statistical difference could be found between the pharmacokinetic parameters, derived from the three‐compartment model, of these preparations. Urinary recovery was continued for a period of 72 h following intravenous or intramuscular OTC administration.

The recovery of OTC in the urine in the 72‐h period was in the range of 73% to 96% of the available dose administered.

The renal OTC clearance, the renal creatinine clearance, the urinary flow, and the interrelationships of these were determined on the basis of urine and plasma data. The mean OTC renal clearance ranged from 482 to 1050 ml/min and the creatinine clearance from 651 to 1304 ml/min. The OTC and creatinine clearances were significantly correlated to the urine flow up to 30 ml/min. The total body clearance and renal clearance values were of the same order of magnitude, and along with the urine recovery data they provided evidence of predominantly renal route of OTC elimination in dairy cows. The renal OTC elimination is the net result of mainly glomerular filtration, partly tubular secretion, minus reabsorption in the urogenital tract.