Body fluid concentrations and pharmacokinetics of chloramphenicol given to mares intravenously or by repeated gavage

Serum concentrations and the pharmacokinetics of chloramphenicol were determined in 6 healthy mares after a single IV administration (50 mg/kg of body weight) or after the 1st and 5th sequential intragastric (IG) administration (50 mg/kg/6 hours) of chloramphenicol. Synovial fluid, peritoneal fluid, CSF, and urinary concentrations of chloramphenicol after the IG administrations also were determined. Mean (+/- SEM) overall elimination rate constant (K) values for the IV, 1st IG, and 5th IG dosages were 0.42 +/- 0.064/hr, 0.42 +/- 0.049/hr, and 0.29 +/- 0.074/hr, respectively, and were not significantly different from one another (P greater than 0.05). Bioavailability was 40 +/- 8.6% after the 1st IG administration and was 21 +/- 5.2% after the 5th IG administration. Values for the area under the curve (AUC) for the 1st and 5th IG dosages were significantly different from the AUC value for the IV dosage, and the AUC value for the 5th IG dosage was significantly different from that for the 1st IG dosage. Chloramphenicol was administered to 2 mares in 6 consecutive doses; the first and last doses were given IV and the others were given IG. Mean K values after the 2 IV doses were 0.38 +/- 0.112/hr and 0.56 +/- 0.078/hr, which were not significantly different from each other or from the mean value for the IV dosage given to all 6 mares. Absorption of chloramphenicol decreased with repeated IG administrations, resulting in lower concentrations of chloramphenicol with subsequent administrations. Five consecutive IG doses of chloramphenicol were administered to 4 of the mares in a separate experiment and did not alter intestinal xylose absorption.     

Amikacin sulfate in mares: pharmacokinetics and body fluid and endometrial concentrations after repeated intramuscular administration

Six mares were given 5 IM injections (at 12-hour intervals between doses) of amikacin sulfate at a dosage of 7 mg/kg of body weight. Serum amikacin concentrations were measured serially throughout the study; synovial, peritoneal, endometrial, and urine concentrations were determined after the last injection. Amikacin concentrations of the CSF were measured serially in 3 of the 6 mares; 1 of the 3 mares had septic meningitis. Mean serum amikacin concentrations peaked at 1 to 2 hours after IM injection. The highest mean serum concentration was 19.2 micrograms/ml (1.5 hours after the 5th injection). The highest mean synovial concentration was 10.8 micrograms/ml at 2 hours after the 5th injection; the highest mean peritoneal concentration was 16.2 micrograms/ml at 3 hours after the 5th injection. The mean endometrial amikacin concentration was 2.5 micrograms/g (1.5 hours after the 5th injection). Amikacin reached a CSF concentration of 0.97 micrograms/ml in the mare with meningitis, but amikacin was not detected in CSF of healthy mares. Urine concentrations reached 1,458 micrograms/ml. Pharmacokinetic values were estimated after the 1st injection (elimination rate constant = 0.31/hour; half-life = 2.3 hours; apparent volume of distribution = 0.26 L/kg), and after the 5th injection (elimination rate constant = 0.28/hour; half-life = 2.6 hours; apparent volume of distribution = 0.30 L/kg); significant differences were not observed.     

Pharmacokinetics and body fluid and endometrial concentrations of cefoxitin in mares

Four healthy adult mares were each given a single injection of sodium cefoxitin (20 mg/kg of body weight, IV), and serum cefoxitin concentrations were measured serially during a 6-hour period. The mean elimination rate constant was 1.08/hour and the elimination half-life was 0.82 hour. The apparent volume of distribution (at steady state) and the clearance of the drug were estimated at 0.12 L/kg and 259 ml/hr/kg, respectively. Each mare and 2 additional mares were then given 4 consecutive IM injections of sodium cefoxitin (400 mg/ml) at a dosage of 20 mg/kg. Cefoxitin concentrations in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium were measured serially. After IM administration, the highest mean serum concentration was 23.1 micrograms/ml 30 minutes after the 2nd injection. The highest mean synovial concentration was 11.4 micrograms/ml 1 hour after the 4th injection. The highest mean peritoneal concentration was 10.4 micrograms/ml 2 hours after the 4th injection. The highest mean endometrial concentration was 4.5 micrograms/g 4 hours after the 4th injection. Mean urine concentrations reached 11,645 micrograms/ml. Cefoxitin did not readily penetrate the CSF. Bioavailability of cefoxitin given IM was 65% to 89% (mean +/- SEM = 77% +/- 5.9%). One of the 6 mares developed acute laminitis during the IM experiment.     

Pharmacokinetics and body fluid and endometrial concentrations of trimethoprim-sulfamethoxazole in mares

Six healthy adult mares were each given a single IV injection of trimethoprim (TMP)-sulfamethoxazole (SMZ) at a dosage of 2.5 mg of TMP/kg of body weight and 12.5 mg of SMZ/kg. Serum concentrations of each drug were measured serially over a 24-hour period. For TMP, the mean overall elimination rate constant (K) was 0.43/hr and the elimination half-life (t1/2) was 1.9 hours. The apparent volume of distribution (at steady state) was 1.62 L/kg and TMP clearance was 886 ml/hr/kg. For SMZ, K was 0.22/hr and t1/2 was 3.53 hours. The apparent volume of distribution at steady state was 0.33 L/kg and SMZ clearance was 78.2 ml/hr/kg. Each mare was then given 5 consecutive oral doses of TMP-SMZ at a rate of 2.5 mg of TMP/kg and 12.5 mg of SMZ/kg at 12-hour intervals. Trimethoprim and SMZ concentrations were measured in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium. Although both mean TMP and SMZ serum concentrations were higher after the 5th dose than after the 1st dose, only the mean TMP concentration was significantly (P less than 0.05) different. After the 5th oral dose, concentrations of TMP and SMZ attained in body fluids (except CSF) and endometrial tissue were equal to or exceeded reported minimum inhibitory concentrations for Corynebacterium pseudotuberculosis, Staphylococcus sp, Streptococcus zooepidemicus, and several obligate anaerobes. Absorption of both drugs was variable after oral administration.     

Pharmacokinetics and body fluid and endometrial concentrations of cephapirin in mares

Six healthy adult horse mares were each given a single injection of sodium cephapirin (20 mg/kg of body weight, IV), and serum cephapirin concentrations were measured serially over a 6-hour period. The mean elimination rate constant was 0.78 hour-1 and the elimination half-life was 0.92 hours. The apparent volume of distribution (at steady state) and the clearance of the drug were estimated at 0.17 L/kg and 598 ml/hour/kg, respectively. Each mare was then given 4 consecutive IM injections of sodium cephapirin (400 mg/ml) at a dosage level of 20 mg/kg. Cephapirin concentrations in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium were measured serially. After IM administration, the highest mean serum concentration was 14.8 micrograms/ml 25 minutes after the 4th injection. The highest mean synovial and peritoneal concentrations were 4.6 micrograms/ml and 5.0 micrograms/ml, respectively, 2 hours after the 4th injection. The highest mean endometrial concentration was 2.2 micrograms/g 4 hours after the 4th injection. Mean urine concentrations reached 7,421 micrograms/ml. Cephapirin did not readily penetrate the CSF. When cephapirin was given IM at the same dose, but in a less concentrated solution (250 mg/ml), serum concentrations peaked at 25.0 micrograms/ml 20 minutes after injection, but the area under the serum concentration-time curve was not significantly different (P greater than 0.05). The bioavailability of the drug was greater than or equal to 95% after IM injection.     

Pharmacokinetics and body fluid and endometrial concentrations of ormetoprim-sulfadimethoxine in mares.

Six healthy adult mares were each given an oral loading dose of ormetoprim(OMP)-sulfadimethoxine (SDM) at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg, followed by four maintenance doses of 4.6 mg of OMP/kg and 22.9 mg of SDM/kg, at 24 h intervals. Ormetoprim and SDM concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid, urine and endometrium. The highest mean serum OMP concentration was 0.92 micrograms/mL 0.5 h after the first dose; the highest mean SDM concentration was 80.9 micrograms/mL 8 h after the first dose. The highest mean synovial fluid concentrations were 0.14 microgram of OMP/mL and 28.5 micrograms of SDM/mL 12 h after the first dose. The highest mean peritoneal fluid concentrations were 0.19 micrograms of OMP/mL 6 h after the first dose and 25.5 micrograms of SDM/mL 8 h after the fifth dose. The highest mean endometrial concentrations were 0.56 micrograms of OMP/g and 28.5 micrograms of SDM/g 4 h after the fifth dose. The mean cerebrospinal fluid concentrations were 0.08 micrograms of OMP/mL and 2.1 micrograms of SDM/mL 5 h after the fifth dose. Mean trough urine drug concentrations were greater than or equal to 0.4 micrograms of OMP/mL and greater than or equal to 172 micrograms of SDM/mL. Two of the mares were each given a single intravenous (IV) injection of OMP and SDM at a dosage of 9.2 mg of OMP/kg and 45.8 mg of SDM/kg. Excitation and muscle fasciculations were observed in both mares after IV administration and all scheduled blood samples could be collected from only one of the two mares.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum concentrations and pharmacokinetics of enrofloxacin after intravenous and intragastric administration to mares.

Serum concentrations and pharmacokinetics of enrofloxacin were studied in 6 mares after intravenous (IV) and intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. In experiment 1, an injectable formulation of enrofloxacin (100 mg/mL) was given IV. At 5 min after injection, mean serum concentration was 9.04 microg/mL and decreased to 0.09 microg/mL by 24 h. Elimination half-life was 5.33 +/- 1.05 h and the area under the serum concentration vs time curve (AUC) was 21.03 +/- 5.19 mg x h/L. In experiment 2, the same injectable formulation was given IG. The mean peak serum concentration was 0.94 +/- 0.97 microg/mL at 4 h after administration and declined to 0.29 +/- 0.12 microg/mL by 24 h. Absorption of this enrofloxacin preparation after IG administration was highly variable, and for this reason, pharmacokinetic values for each mare could not be determined. In experiment 3, a poultry formulation (32.3 mg/mL) was given IG. The mean peak serum concentration was 1.85 +/- 1.47 microg/mL at 45 min after administration and declined to 0.19 +/- 0.06 microg/mL by 24 h. Elimination half-life was 10.62 +/- 5.33 h and AUC was 16.30 +/- 4.69 mg x h/L. Bioavailability was calculated at 78.29 +/- 16.55%. Minimum inhibitory concentrations of enrofloxacin were determined for equine bacterial culture specimens submitted to the microbiology laboratory over an 11-month period. The minimum inhibitory concentration of enrofloxacin required to inhibit 90% of isolates (MIC90) was 0.25 microg/mL for Staphylococcus aureus, Escherichia coli, Salmonella spp., Klebsiella spp., and Pasteurella spp. The poultry formulation was well tolerated and could be potentially useful in the treatment of susceptible bacterial infections in adult horses. The injectable enrofloxacin solution should not be used orally.     

Pharmacokinetics of difloxacin and its concentration in body fluids and endometrial tissues of mares after repeated intragastric administration

Pharmacokinetics of difloxacin and its distribution within the body fluids and endometrium of 6 mares were studied after intragastric (IG) administration of 5 individual doses. Difloxacin concentrations were serially measured in serum, urine, peritoneal fluid, synovial fluid, cerebrospinal fluid, and endometrium over 120 h. Bacterial susceptibility to difloxacin was determined for 174 equine pathogens over a 7-month period. Maximum serum concentration (Cmax) was 2.25 +/- 0.70 microg/mL at 3.12 +/- 2.63 h and Cmax after the 5th dose was 2.41 +/- 0.86 microg/mL at 97.86 +/- 1.45 h. The mean elimination half-life (t(1/2)) was 8.75 +/- 2.77 h and area under the serum concentration versus time curve (AUC) was 25.13 +/- 8.79 microg h/mL. Highest mean synovial fluid concentration was 1.26 +/- 0.49 microg/mL at 100 h. Highest mean peritoneal fluid concentration was 1.50 +/- 0.56 microg/mL at 98 h. Highest mean endometrial concentration was 0.78 +/- 0.48 microg/g at 97.5 h. Mean cerebrospinal fluid concentration was 0.87 +/- 0.52 microg/mL at 99 h. Highest mean urine concentration was 92.05 +/- 30.35 microg/mL at 104 h. All isolates of Salmonella spp. and Pasteurella spp. were susceptible. In general, gram-negative organisms were more susceptible than gram-positives. Difloxacin appears to be safe, adequately absorbed, and well distributed to body fluids and endometrial tissues of mares and may be useful in the treatment of susceptible bacterial infections in adult horses.     

Endometrial and serum gentamicin concentrations in pony mares given repeated intrauterine infusions

Endometrial tissue and blood serum gentamicin (GT) concentrations were determined in 6 ovariectomized pony mares given intrauterine infusions (50 ml of a 5% commercial aqueous solution of GT) each day for 5 consecutive days. The mares were subjected to the following 3 treatments: (1) GT infusion only (trial A, control); (2) progesterone plus GT (trial B, P + G); and (3) estradiol plus GT (trial C, E + G). Endometrial tissue concentrations of GT (micrograms/g) at 24 and 120 hours were significantly higher (P less than 0.05) in trials B (65.54 +/- 15.57 and 100.33 +/- 19.27) and C (73.33 +/- 22.53 and 74.09 +/- 8.60) than in trial A (4.23 +/- 0.70). Endometrial concentration for trial A at 120 hours was also significantly higher than trial A at 24 hours. There was no significant difference (P greater than 0.05) in endometrial concentrations among trials A, B, and C at 120 hours. Serum GT concentrations were significantly lower than endometrial tissue concentrations. The highest serum concentrations of GT found in every trial occurred at 6 hours after each intrauterine infusion of GT. The highest overall serum concentration of GT (micrograms/ml) determined occurred in trial B (8.30 +/- 1.28) at 78 hours. There was no significant difference in serum concentrations of GT between days of treatment, except for trial A at 78 and 102 hours, respectively. Serum concentrations of GT were significantly higher (P less than 0.05) than trial A at 30, 54, 78, and 102 hours in trial B, and at 78 and 102 hours in trial C. There was no significant difference in serum concentrations of GT between trials B and C.     

Single-dose pharmacokinetics of cefazolin in bovine synovial fluid after intravenous regional injection

Gagnon, H., Ferguson, J.G., Papich, M.G., Bailey, J.V. Single-dose pharmacokinetics of cefazolin in bovine synovial fluid after intravenous regional injection. J. vet. Pharmacol. Therap. 17, 31–37.
The pharmacokinetic properties of cefazolin in the synovial fluid of the tibiotarsal joint were determined in 10 healthy mature cattle after intravenous regional injection of 2 50 mg cefazolin. A pneumatic tourniquet was positioned proximal to the tibiotarsal joint and the intravenous injection was performed distal to the tourniquet. Synovial fluid concentrations of cefazolin increased in the first 30 mm and fluctuated between 54.7 ± 11.0 g/ml (mean ± SEM) and 73.2 ± 13.2 g/ml in the following 90 min while the tourniquet remained inflated. After tourniquet removal, synovial fluid concentration-time curves followed first-order one-compartment model decay in most of the animals with an elimination half-life of 0.82 h (harmonic mean). Therapeutic concentrations of cefazolin in the synovial fluid of normal joints were reached and this injection technique could be used as an alternative to systemic administration of antibiotics to provide adequate concentrations in a localized area.     

Synovial fluid and plasma concentrations of ceftiofur after regional intravenous perfusion in the horse

OBJECTIVE: To determine radiocarpal (RC) joint synovial fluid and plasma ceftiofur concentrations after regional intravenous perfusion (RIP) and systemic intravenous (IV) administration. STUDY DESIGN: Experimental cross-over study. ANIMALS: Five normal adult horses. METHODS: One RC joint was randomly selected for RIP and the contralateral RC joint was sampled to determine intrasynovial ceftiofur concentrations after IV administration. Wash-out between IV and RIP was > or = 14 days. After surgical introduction of an intraarticular catheter, ceftiofur (2 g) was administered under general anesthesia either IV or by RIP after tourniquet application. Plasma and synovial fluid were collected over 24 hours. Samples were analyzed using high-performance liquid chromatography with ultraviolet detection and the results were statistically analyzed using a linear mixed effect model. RESULTS: Mean synovial fluid ceftiofur concentrations were consistently higher after RIP than after IV administration and were > 1 mug/mL (minimal inhibitory concentration [MIC] for common pathogens) for >24 hours. Mean synovial fluid peak concentration of ceftiofur after RIP and IV administration was 392.7+/-103.29 microg/mL at 0.5 hours postinjection (HPI) and 2.72+/-0.31 mug/mL at 1 HPI, respectively. Large variations in synovial fluid and plasma ceftiofur concentrations were observed between horses regardless of administration technique. RIP did not cause adverse effects. CONCLUSIONS: Under the present experimental conditions RIP with ceftiofur (2 g) induced significantly higher intraarticular antibiotic concentrations in the RC joint in comparison with IV administration. Moreover, after RIP, synovial fluid ceftiofur concentrations remain above the MIC for common pathogens (1 microg/mL) for > 24 hours. No adverse effects from the technique or the antibiotic were observed. CLINICAL RELEVANCE: RIP with high doses of ceftiofur may be a beneficial adjunctive therapy when treating equine synovial infections which are caused by cephalosporin susceptible microorganisms.     

Effect of repeated collection of multiple endometrial biopsy specimens on subsequent pregnancy in mares.

Endometrial biopsy specimens (4 or 5 on each occasion) were collected from 7 mares 2, 3, or 4 times over a 50-day period prior to breeding. Four of the collection days were within 6 days of breeding. Six of the 7 mares were diagnosed as pregnant by use of ultrasonography at day 14 after ovulation. This pregnancy rate was the same as that achieved by these mares when they were bred at estrus before the start of the study. It appeared that repeated collection of multiple endometrial biopsy specimens from genitally normal mares did not adversely affect pregnancy rate.     

Plasma pharmacokinetics and tissue fluid concentrations of meropenem after intravenous and subcutaneous administration in dogs

OBJECTIVE: To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURE: Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device. RESULTS: Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean +/- SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 +/- 0.07 hours, 0.372 +/- 0.053 L/kg, and 6.53 +/- 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 +/- 0.57 hours. Half-life after SC administration was 0.98 +/- 0.21 and 1.31 +/- 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 microg/mL.     

Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations of fluconazole following repeated oral dosing in horses

OBJECTIVE: To determine the pharmacokinetics of fluconazole in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Fluconazole (10 mg/kg of body weight) was administered intravenously or orally with 2 weeks between treatments. Plasma fluconazole concentrations were determined prior to and 10, 20, 30, 40, and 60 minutes and 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after administration. A long-term oral dosing regimen was designed in which all horses received a loading dose of fluconazole (14 mg/kg) followed by 5 mg/kg every 24 hours for 10 days. Fluconazole concentrations were determined in aqueous humor, plasma, CSF, synovial fluid, and urine after administration of the final dose. RESULTS: Mean (+/- SD) apparent volume of distribution of fluconazole at steady state was 1.21+/-0.01 L/kg. Systemic availability and time to maximum plasma concentration following oral administration were 101.24+/-27.50% and 1.97+/-1.68 hours, respectively. Maximum plasma concentrations and terminal half-lives after IV and oral administration were similar. Plasma, CSF, synovial fluid, aqueous humor, and urine concentrations of fluconazole after long-term oral administration of fluconazole were 30.50+/-23.88, 14.99+/-1.86, 14.19+/-5.07, 11.39+/-2.83, and 56.99+/-32.87 microg/ml, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bioavailability of fluconazole was high after oral administration to horses. Long-term oral administration maintained plasma and body fluid concentrations of fluconazole above the mean inhibitory concentration (8.0 mg/ml) reported for fungal pathogens in horses. Fluconazole may be an appropriate agent for treatment of fungal infections in horses.     

Pharmacokinetics of voriconazole following intravenous and oral administration and body fluid concentrations of voriconazole following repeated oral administration in horses

OBJECTIVE: To determine the pharmacokinetics of voriconazole following IV and PO administration and assess the distribution of voriconazole into body fluids following repeated PO administration in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURES: All horses received voriconazole (10 mg/kg) IV and PO (2-week interval between treatments). Plasma voriconazole concentrations were determined prior to and at intervals following administration. Subsequently, voriconazole was administered PO (3 mg/kg) twice daily for 10 days to all horses; plasma, synovial fluid, CSF, urine, and preocular tear film concentrations of voriconazole were then assessed. RESULTS: Mean +/- SD volume of distribution at steady state was 1,604.9 +/- 406.4 mL/kg. Systemic bioavailability of voriconazole following PO administration was 95 +/- 19%; the highest plasma concentration of 6.1 +/- 1.4 microg/mL was attained at 0.6 to 2.3 hours. Mean peak plasma concentration was 2.57 microg/mL, and mean trough plasma concentration was 1.32 microg/mL. Mean plasma, CSF, synovial fluid, urine, and preocular tear film concentrations of voriconazole after long-term PO administration were 5.163 +/- 1.594 microg/mL, 2.508 +/- 1.616 microg/mL, 3.073 +/- 2.093 microg/mL, 4.422 +/- 0.8095 microg/mL, and 3.376 +/- 1.297 microg/mL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that voriconazole distributed quickly and widely in the body; following a single IV dose, initial plasma concentrations were high with a steady and early decrease in plasma concentration. Absorption of voriconazole after PO administration was excellent, compared with absorption after IV administration. Voriconazole appears to be another option for the treatment of fungal infections in horses.     

Pharmacokinetics of ketoprofen after multiple intravenous doses to mares

The pharmacokinetics and urinary excretion of ketoprofen in six healthy mares after the first and last of five daily intravenous doses of 2.2 mg of ketoprofen per kg body weight were investigated using a high-performance liquid chromatographic (HPLC) method for determining plasma and urinary ketoprofen concentrations. Plasma ketoprofen concentrations declined triexponentially after each dose with no significant differences in plasma concentrations or pharmacokinetic parameter values between the first and last doses. The harmonic mean of the terminal elimination half-life of ketoprofen after the first and last dose was 98.2 and 78.0 min, respectively. The median values of the total plasma clearance and the renal clearance after the first dose were 4.81 and 1.93 mL/min/kg, respectively. Total plasma clearance was attributed to renal excretion of ketoprofen and metabolism of ketoprofen to a base-labile conjugate which was also excreted in the urine. Renal clearance of ketoprofen was attributed to renal tubular secretion since renal clearance was greater than filtration clearance. Urinary recovery of ketoprofen during the first 420 min after the first dose accounted for 26.4% of the dose as unconjugated ketoprofen and 29.8% of the dose as a base-labile conjugate of ketoprofen. Total urinary recovery of ketoprofen as unchanged ketoprofen and from base-labile conjugate represented 56.2% of the dose. Plasma protein binding of ketoprofen was extensive; the mean plasma protein binding of ketoprofen was 92.8% (SD 3.0%) at 500 ng/mL and 91.6% (SD 0.60%) at 10.0 μg/mL.     

Pharmacokinetics and endometrial tissue concentrations of enrofloxacin and the metabolite ciprofloxacin after i.v. administration of enrofloxacin to mares

Enrofloxacin was administered i.v. to five adult mares at a dose of 5 mg/kg. After administration, blood and endometrial biopsy samples were collected at regular intervals for 24 h. The plasma and tissue samples were analyzed for enrofloxacin and the metabolite ciprofloxacin by high-pressure liquid chromatography. In plasma, enrofloxacin had a terminal half-life (t(1/2)), volume of distribution (area method), and systemic clearance of 6.7 +/- 2.9 h, 1.9 +/- 0.4 L/kg, and 3.7 +/- 1.4 mL/kg/min, respectively. Ciprofloxacin had a maximum plasma concentration (Cmax) of 0.28 +/- 0.09 microg/mL. In endometrial tissue, the enrofloxacin Cmax was 1.7 +/- 0.5 microg/g, and the t(1/2) was 7.8 +/- 3.7 h. Ciprofloxacin Cmax in tissues was 0.15 +/- 0.04 microg/g and the t(1/2) was 5.2 +/- 2.0 h. The tissue:plasma enrofloxacin concentration ratios (w/w:w/v) were 0.175 +/- 0.08 and 0.47 +/- 0.06 for Cmax and AUC, respectively. For ciprofloxacin, these values were 0.55 +/- 0.13 and 0.58 +/- 0.31, respectively. We concluded that plasma concentrations achieved after 5 mg/kg i.v. are high enough to meet surrogate markers for antibacterial activity (Cmax:MIC ratio, and AUC:MIC ratio) considered effective for most susceptible gram-negative bacteria. Endometrial tissue concentrations taken from the mares after dosing showed that enrofloxacin and ciprofloxacin both penetrate this tissue adequately after systemic administration and would attain concentrations high enough in the tissue fluids to treat infections of the endometrium caused by susceptible bacteria.     

Changes in serum concentrations of luteinizing hormone and follicle-stimulating hormone following injection of gonadotropin-releasing hormone during pregnancy and after parturition in mares

High concentrations of estrogens in the peripheral circulation during late gestation inhibit synthesis of LH and markedly reduce pituitary content of LH at the end of pregnancy in most domestic species. Because blood concentrations of estrogen peak shortly before mid-gestation in the mare and then gradually decrease until parturition, we hypothesized that pituitary content of LH may increase during late gestation. To test this hypothesis 10 horse mares were challenged with a maximally stimulatory dose (2 micrograms/kg) of GnRH on d 240 and 320 of gestation and d 3 after parturition. A separate group of four mares were treated with GnRH on d 2 or 3 estrus. Blood samples were collected at -2, -1, 0, .25, .5, .75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7 and 8 h relative to injection of GnRH and serum was analyzed for concentration of LH and FSH. Basal serum concentration and total quantity of LH released after GnRH stimulation (assessed by determining the area under the response curve) were not different on d 240 and 320 of gestation or on d 3 after parturition (12.5 +/- 3.5, 5.7 +/- 1.5 and 29.1 +/- 12.1 ng.min/ml, respectively) and were less (P less than .05) than on d 3 of estrus (311.0 +/- 54.0 ng.min/ml). There was little difference in the basal serum concentration of FSH at any of the time points examined. In contrast, GnRH-induced release of FSH continually decreased (P less than .05) from d 240 of gestation (559.8 +/- 88.9 ng.min/ml) to d 3 of estrus (51.8 +/- 6.2 ng.min/ml).(ABSTRACT TRUNCATED AT 250 WORDS)