Study of intragastric administration of doxycycline: pharmacokinetics including body fluid, endometrial and minimum inhibitory concentrations

The objectives of this study were to determine the pharmacokinetics and tissue concentrations of doxycycline after repeated intragastric administration, and to determine the minimum inhibitory concentrations (MIC) for equine pathogenic bacteria. In experiment 1, 2 mares received a single intragastric dose of doxycycline hyclate (3 mg/kg bwt). Mean peak serum concentration was 0.22 microg/ml 1 h postadministration. In experiment 2, 5 doses of doxycycline hyclate (10 mg/kg bwt), dissolved in water, were administered to each of 6 mares via nasogastric tube at 12 h intervals. The mean +/- s.e. peak serum doxycycline concentration was 0.32+/-0.16 microg/ml 1 h after the first dose and 0.42+/-0.05 microg/ml 2 h after the fifth dose. The mean trough serum concentrations were > 0.16 microg/ml. Highest mean synovial concentration was 0.46+/-0.13 microg/ml and highest mean peritoneal concentration was 0.43+/-0.07 microg/ml, both 2 h after the fifth dose. Highest urine concentration was mean +/- s.e. 145+/-25.4 microg/ml 2 h after the last dose. Highest endometrial concentration was mean +/- s.e. 1.30+/-0.36 microg/ml 3 h after the fifth dose. Doxycycline was not detected in any of the CSF samples. Mean +/- s.e. Vd(area) was 25.3+/-5.0 l/kg and mean t1/2 was 8.7+/-1.6 h. In experiment 3, minimum inhibitory concentrations of doxycycline were determined for 168 equine bacterial culture specimens. The MIC90 was < or = 1.0 microg/ml for Streptococcus zooepidemicus and 0.25 microg/ml for Staphylococcus aureus. Based on drug concentrations achieved in the serum, synovial and peritoneal fluids and endometrial tissues and MIC values determined in the present study, doxycycline at a dose of 10 mg/kg bwt per os every 12 h may be appropriate for the treatment of infections caused by susceptible (MIC < 0.25 microg/ml) gram-positive organisms in horses.     

Effect of probenecid administration on cephapirin pharmacokinetics and concentrations in mares

Cephapirin (20 mg/kg of body weight, IV) was administered before and after 3 doses of probenecid (25, 50, or 75 mg/kg, intragastrically, at 12-hour intervals) to 2 mares. Clearance and apparent volume of distribution, based on area under the curve, were negatively correlated with probenecid dose. Clearance of cephapirin was decreased by approximately 50% by administration of 50 mg of probenecid/kg. Serum, synovial fluid, peritoneal fluid, CSF, urinary, and endometrial concentrations of cephapirin were determined after 5 doses of cephapirin (20 mg/kg, IM, at 12-hour intervals) without and with concurrently administered probenecid (50 mg/kg, intragastrically) to 6 mares, including the 2 mares given cephapirin, IV. Highest mean serum cephapirin concentrations were 16.1 +/- 2.16 micrograms/ml at 0.5 hour after the 5th cephapirin dose [postinjection (initial) hour (PIH) 48.5] in mares not given probenecid and 23.7 +/- 1.30 micrograms/ml at 1.5 hours after the 5th cephapirin dose (PIH 49.5) in mares given probenecid. Mean peak peritoneal fluid and synovial fluid cephapirin concentrations were 6.2 +/- 0.57 micrograms/ml and 6.6 +/- 0.58 micrograms/ml, respectively, without probenecid administration and 12.3 +/- 0.46 micrograms/ml and 10 +/- 0.78 micrograms/ml, respectively, with concurrent probenecid administration. Mean trough cephapirin concentrations for peritoneal and synovial fluids in mares given probenecid were 2 to 3 times higher than trough concentrations in mares not given probenecid. Overall mean cephapirin concentrations were significantly higher for serum, peritoneal fluid, synovial fluid, and endometrium when probenecid was administered concurrently with cephapirin (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Pharmacokinetics of metronidazole and its concentration in body fluids and endometrial tissues of mares.

Serum concentrations of metronidazole were determined in 6 healthy adult mares after a single IV injection of metronidazole (15 mg/kg of body weight). The mean elimination rate (K) was 0.23 h-1, and the mean elimination half-life (t1/2) was 3.1 hours. The apparent volume of distribution at steady state was 0.69 L/kg, and the clearance was 168 ml/h/kg. Each mare was then given a loading dose (15 mg/kg) of metronidazole at time 0, followed by 4 maintenance doses (7.5 mg/kg, q 6 h) by nasogastric tube. Metronidazole concentrations were measured in serial samples of serum, synovia, peritoneal fluid, and urine. Metronidazole concentrations in CSF and endometrial tissues were measured after the fourth maintenance dose. The highest mean concentration in serum was 13.9 +/- 2.18 micrograms/ml at 40 minutes after the loading dose (time 0). The highest mean synovial and peritoneal fluid concentrations were 8.9 +/- 1.31 micrograms/ml and 12.8 +/- 3.21 micrograms/ml, respectively, 2 hours after the loading dose. The lowest mean trough concentration in urine was 32 micrograms/ml. Mean concentration of metronidazole in CSF was 4.3 +/- 2.51 micrograms/ml and the mean concentration in endometrial tissues was 0.9 +/- 0.48 micrograms/g at 3 hours after the fourth maintenance dose. Two mares hospitalized for treatment of bacterial pleuropneumonia were given metronidazole (15.0 mg/kg, PO, initially then 7.5 mg/kg, PO, q 6 h), while concurrently receiving gentamicin, potassium penicillin, and flunixin meglumine IV. Metronidazole pharmacokinetics and serum concentrations in the sick mares were similar to those obtained in the healthy mares.     

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.     

Gentamicin sulfate in the horse: serum, synovial, peritoneal, and urine concentrations after single dose intramuscular administration

Ten healthy adult mares were given a single intramuscular dose (2.2 mg/kg) of gentamicin sulfate. Over a 48-h period, gentamicin concentrations were measured serially in the serum of all ten mares and in synovial fluid, peritoneal fluid, and urine of six of the mares. The mean peak serum gentamicin concentration was 5.73 μg/ml at 1 h. Gentamicin was detected in synovial fluid and peritoneal fluid, with mean peak gentamicin concentrations of 2.41 μg/ml and 3.92 μg/ml, respectively, observed at 2 h. These concentrations declined in parallel with serum concentrations and were not measurable at 48 h. Urine gentamicin concentration was relatively high, with a mean peak concentration of 424.9 μg/ml at 1 h after drug administration.     

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.     

Chloramphenicol sodium succinate in the horse: serum, synovial, peritoneal, and urine concentrations after single-dose intravenous administration

Six healthy adult mares were given a single IV dose (25 mg/kg of body weight) of chloramphenicol sodium succinate. Chloramphenicol concentrations in serum, synovial fluid, peritoneal fluid, and urine were measured serially over a 48-hour period. The highest measured serum chloramphenicol concentration was 6.21 micrograms/ml at 0.5 hour. Chloramphenicol was detected in synovial and peritoneal fluids, with mean peak concentrations of 3.89 micrograms/ml and 3.50 micrograms/ml, respectively, at 0.5 hour. Serum and synovial concentrations declined rapidly and were not measurable at 3 hours. Chloramphenicol could not be detected in peritoneal fluid at 6 hours. The serum half-life was 0.43 hour and the apparent volume of distribution was 2.83 L/kg. Urine concentrations of chloramphenicol peaked at 0.5 hour at 106.72 micrograms/ml and also declined rapidly. The drug could not be detected in the urine at 36 hours.     

Oxytetracycline hydrochloride in the horse: serum, synovial, peritoneal and urine concentrations after single dose intravenous administration

Six adult mares were given a single intravenous injection of oxytetracycline HCl (50 mg/ml) at a dosage of 5 mg/kg. Serum, synovial fluid, peritoneal fluid, and urine oxytetracycline concentrations were measured serially over a 48-h period. The highest measured serum oxytetracycline concentration was 8.01 mcg/ml at 1/2 h. Oxytetracycline was detected in synovial fluid and peritoneal fluid, which obtained mean peak oxytetracycline concentrations of 4.43 mcg/ml and 4.20 mcg/ml, at 1/2 h and 1 h, respectively. These concentrations steadily declined in parallel with serum concentrations and were not measurable at 48 h. Urine oxytetracycline concentration was relatively high, with a peak concentration of 1565.2 mcg/ml at 1/2 h after drug administration.     

Pharmacokinetics and distribution of minocycline in mature horses after oral administration of multiple doses and comparison with minimum inhibitory concentrations

Reasons for performing study: Minocycline holds great potential for use in horses not only for its antimicrobial effects but also for its anti‐inflammatory and neuroprotective properties. However, there are no pharmacokinetic or safety data available regarding the use of oral minocycline in horses. Objectives: To determine pharmacokinetics, safety and penetration into plasma, synovial fluid, aqueous humour (AH) and cerebral spinal fluid (CSF) of minocycline after oral administration of multiple doses in horses and to determine the minimum inhibitory concentrations (MIC) of minocycline for equine pathogenic bacteria. Methods: Six horses received minocycline (4 mg/kg bwt q. 12 h for 5 doses). Thirty‐three blood and 9 synovial fluid samples were collected over 96 h. Aqueous humour and CSF samples were collected 1 h after the final dose. Minocycline concentrations were measured using high pressure liquid chromatography. The MIC values of minocycline for equine bacterial isolates were determined. Results: At steady state, the mean ± s.d. peak concentration of minocycline in the plasma was 0.67 ± 0.26 µg/ml and the mean half‐life was 11.48 ± 3.23 h. The highest trough synovial fluid minocycline concentration was 0.33 ± 0.12 µg/ml. The AH concentration of minocycline was 0.09 ± 0.03 µg/ml in normal eyes and 0.11 ± 0.04 µg/ml in blood aqueous barrier‐disrupted eyes. The mean CSF concentration of minocycline was 0.38 ± 0.09 µg/ml. The MIC values were determined for 301 isolates. Minocycline concentrations were above the MIC₅₀ and MIC₉₀ for many gram‐positive equine pathogens. Potential relevance: This study supports the use of orally administered minocycline at a dose of 4 mg/kg bwt every 12 h for the treatment of nonocular infections caused by susceptible (MIC≤0.25 µg/ml) organisms in horses. Further studies are required to determine the dose that would be effective for the treatment of ocular infections.     

Pharmacokinetics and bioequivalence of two suxibuzone oral dosage forms in horses

A disposition and bioequivalence study with a suxibuzone granulated and a suxibuzone paste oral formulation was performed in horses. Suxibuzone (SBZ) is a nonsteroidal anti-inflammatory drug, which was administered to horses (n = 6) at a dosage of 19 mg/kg bwt by the oral route (p.o.) in a two period cross-over design. Suxibuzone is very rapidly transformed into its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ). Therefore plasma and synovial fluid concentrations of SBZ, PBZ and OPBZ were simultaneously measured by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Suxibuzone could not be detected in any plasma and synovial fluid samples (< 0.04 microgram/mL). Plasma PBZ and OPBZ concentrations were detected between 30 min and 72 h after granulate and paste administration. Mean plasma concentration of PBZ peaked at 5 h (34.5 +/- 6.7 micrograms/mL) and at 7 h (38.8 +/- 8.4 micrograms/mL), and mean area under the concentration-time curve (AUC0-->LOQ) was 608.0 +/- 162.2 micrograms.h/mL and 656.6 +/- 149.7 micrograms.h/mL after granulate and paste administration, respectively. Mean plasma concentration of OPBZ increased to 5-6.7 micrograms/mL, with the maximum concentration (Cmax) appearing between 9 and 12 h after administration of both formulations. The AUCs0-->LOQ for OPBZ were also similar (141.8 +/- 48.3 micrograms.h/mL granulate vs. 171.4 +/- 45.0 micrograms.h/mL paste). It was concluded that the suxibuzone products were bioequivalent with respect to PBZ. For OPBZ, the 95% confidence intervals of the pharmacokinetic parameters were within the acceptable range of 80-125%. The paste formulation provided greater bioavailability of PBZ and OPBZ.     

Bioavailability of oral penicillins in the horse: a comparison of pivampicillin and amoxicillin

The pharmacokinetics of ampicillin and amoxicillin following intravenous administration at a dose rate of 15 and 10 mg/kg respectively were studied in four healthy adult horses. Pharmacokinetics of pivampicillin and amoxicillin were studied after oral administration to four healthy adult horses. Pivampicillin, a prodrug of ampicillin, was administered orally to starved and fed horses at a dose rate of 19.9 mg/kg, which is equivalent on a molecular basis to 15 mg/kg ampicillin. Amoxicillin was administered orally to starved horses only, at a dose rate of 20 mg/kg. Ampicillin and amoxicillin concentrations in plasma, synovial fluid and urine were determined. Mean biological half-life of intravenously administered ampicillin and amoxicillin was 1.72 and 1.43 h respectively, whilst the distribution volume (Vss) appeared to be 0.180 and 0.192 1/kg. Orally administered pivampicillin and amoxicillin were rapidly absorbed. A maximum concentration in plasma of 3.80 micrograms/ml was reached 2 h after administration of pivampicillin to starved horses; in fed horses a maximum concentration of 5.12 micrograms/ml was reached 1 h after administration. After oral administration of amoxicillin a maximum concentration of 2.03 micrograms/ml was reached after 1 h. The (absolute) bioavailability of pivampicillin administered orally was 30.9% in starved horses and 35.9% in fed horses. The bioavailability of amoxicillin administered orally was 5.3% in starved horses.     

Pharmacokinetics of amikacin in plasma and selected body fluids of healthy horses after a single intravenous dose

Reasons for performing study: No studies have determined the pharmacokinetics of low‐dose amikacin in the mature horse. Objectives: To determine if a single i.v. dose of amikacin (10 mg/kg bwt) will reach therapeutic concentrations in plasma, synovial, peritoneal and interstitial fluid of mature horses (n = 6). Methods: Drug concentrations of amikacin were measured across time in mature horses (n = 6); plasma, synovial, peritoneal and interstitial fluid were collected after a single i.v. dose of amikacin (10 mg/kg bwt). Results: The mean ± s.d. of selected parameters were: extrapolated plasma concentration of amikacin at time zero 144 ± 21.8 µg/ml; extrapolated plasma concentration for the elimination phase 67.8 ± 7.44 µg/ml, area under the curve 139 ± 34.0 µg*h/ml, elimination half‐life 1.34 ± 0.408 h, total body clearance 1.25 ± 0.281 ml/min/kg bwt; and mean residence time (MRT) 1.81 ± 0.561 h. At 24 h, the plasma concentration of amikacin for all horses was below the minimum detectable concentration for the assay. Selected parameters in synovial and peritoneal fluid were maximum concentration (C_max) 19.7 ± 7.14 µg/ml and 21.4 ± 4.39 µg/ml and time to maximum concentration 65 ± 12.2 min and 115 ± 12.2 min, respectively. Amikacin in the interstitial fluid reached a mean peak concentration of 12.7 ± 5.34 µg/ml and after 24 h the mean concentration was 3.31 ± 1.69 µg/ml. Based on a minimal inhibitory concentration (MIC) of 4 µg/ml, the mean C_max : MIC ratio was 16.9 ± 1.80 in plasma, 4.95 ± 1.78 in synovial fluid, 5.36 ± 1.10 in peritoneal fluid and 3.18 ± 1.33 in interstitial fluid. Conclusions: Amikacin dosed at 10 mg/kg bwt i.v. once a day in mature horses is anticipated to be effective for treatment of infection caused by most Gram‐negative bacteria. Potential relevance: Low dose amikacin (10 mg/kg bwt) administered once a day in mature horses may be efficacious against susceptible microorganisms.     

Synovial fluid and plasma kinetics of methylprednisolone and methylprednisolone acetate in horses following intra-articular administration of methylprednisolone acetate

Synovial fluid and plasma kinetics of methylprednisolone acetate (MPA) and methylprednisolone (MP) after a single intra-articular administration of MPA at a therapeutic dose (111 mg in toto) was measured in five horses. MPA was detected in synovial fluid for two to six days post injection and MP, which results from synovial MPA hydrolysis, was present in pharmacologically significant concentrations for 4.8 to 39 days, depending on the horse. MPA synovial concentration was maximal (289 +/- 284 micrograms/ml) at the first sampling time (2 h after administration) and MP synovial concentration was maximal (from 58.9 to 379.5 micrograms/ml) at the first or second sampling time (2 to 10 h after administration). Thereafter, both MP and MPA declined rapidly. From time of administration to about five days later, MP synovial fluid concentration fell progressively with a half-time of 9.95 h. Subsequently, the MP synovial fluid concentration decreased more slowly with an apparent half-time of 115 h. During the first 24 h following MPA administration, trace amounts of MP (less than 5 ng/ml) were detected in plasma. Plasma hydrocortisone levels were depressed for three to four days after administration but adrenal responsiveness to adrenocorticotrophic hormone tests remained unaffected.     

Effect of induced synovial inflammation on pharmacokinetics and synovial concentration of sodium ampicillin and kanamycin sulfate after systemic administration in ponies

Single doses of sodium ampicillin (10 mg/kg) and kanamycin sulfate (5 mg/kg) were administered intramuscularly (i.m.) separately, and then together, to five pony mares. The plasma antibiotic concentration-time curves were constructed. The pharmacokinetic parameters of the antibiotics given separately were not altered by concurrent administration. Four of the five pony mares were then given the i.m. kanamycin/ampicillin combination 4 h after acute synovitis and fever had been induced by injection of lipopolysaccharide into the left intercarpal joint. The plasma concentration-time curves and the synovial concentration-time curves of inflamed and normal joints were constructed. The Cmax of ampicillin in the lipopolysaccharide experiment was significantly higher than in the other experiments. The antibiotics entered the synovial fluid of the inflamed joints more quickly and attained higher concentrations than in the uninflamed joints. The ampicillin concentration exceeded 5 micrograms/ml in inflamed synovial fluid for some 2.5 h after injection, and kanamycin sulfate concentration exceeded 2 micrograms/ml for 7 h.     

Pharmacokinetics and synovial fluid concentrations of cephapirin in calves with suppurative arthritis

Six calves with suppurative arthritis were given a single IM injection of sodium cephapirin at a dosage of 10 mg/kg of body weight. Cephapirin concentrations were serially measured in serum and in normal and suppurative synovial fluid over a 24-hour period. Mean peak serum concentration was 6.33 microliters/ml at 20 minutes after injection. The highest cephapirin concentrations in normal and suppurative synovial fluid were 1.68 and 1.96 micrograms/ml, respectively, 30 minutes after injection. Overall mean cephapirin concentration in normal synovial fluid for the first 4 hours (1.04 +/- 0.612 micrograms/ml) was not significantly different from that in suppurative synovial fluid (0.88 +/- 0.495 micrograms/ml; P greater than 0.05). Elimination half-life was 0.60 hours and clearance was 1,593 ml/h/kg.     

Preliminary study on the pharmacokinetics of phenobarbital in the neonatal foal

Pharmacokinetic characteristics of the anticonvulsant phenobarbital were studied in seven pony and two Thoroughbred foals aged between four and 10 days. A single, 20 mg/kg bodyweight (bwt) dose of phenobarbital was given intravenously over 25 mins and the serum concentrations of the drug were measured using an EMIT AED assay (coefficient of variation 1.37 per cent at 30 micrograms/ml, n = 7). Phenobarbital elimination was found to follow first order kinetics. The mean (+/- sd) peak phenobarbital serum concentration was 18.6 +/- 2.1 micrograms/ml at 1 h after initiation of infusion with a mean (+/- se) half-life of 12.8 +/- 2.1 h. The mean (+/- se) volume of distribution was 0.86 +/- 0.026 litres/kg bwt and mean (+/- se) total body clearance was 0.0564 +/- 0.0065 litres/kg bwt/h. Sedation was noticed 15 to 20 mins after the beginning of infusion and lasted for up to 8 h. All foals could be aroused and could walk although they were ataxic for the first 1 to 2 h. A degree of delayed hyperexcitability occurred 3 to 8 h after infusion. In equine neonatal seizure disorders it is recommended to use a loading dose of 20 mg/kg bwt of phenobarbital, followed by maintenance doses of 9 mg/kg bwt at 8 h. With this regimen, average steady state serum phenobarbital concentrations should range between approximately 11.6 and 53 micrograms/ml. Phenobarbital serum concentrations should be monitored following the loading dose and 24 h after initiating the maintenance doses to check that levels remain within the suggested (human) therapeutic range of 15 to 40 micrograms/ml.     

Serum and synovial fluid concentrations of ampicillin trihydrate in calves with suppurative arthritis

Eight calves with suppurative arthritis were each given a single intramuscular injection of ampicillin trihydrate at a dose of 10 mg/kg. Ampicillin concentrations were measured serially in serum and in suppurative and normal synovial fluid over a 24-hour period. The mean peak serum concentration was 2.5 +/- 0.54 micrograms/ml 2 hours after injection. The highest concentration in normal synovial fluid was 3.5 +/- 0.40 micrograms/ml at 4 hours and the highest concentration in suppurative synovial fluid was 2.7 +/- 0.58 micrograms/ml at 2 hours. Overall mean ampicillin concentration in normal synovial fluid for the first 8 h (2.9 +/- 0.32 micrograms/ml) was significantly different from that in suppurative synovial fluid (2.1 +/- 0.33 micrograms/ml) and serum (1.9 +/- 0.30 micrograms/ml; p less than 0.05).     

Pharmacokinetics of orbifloxacin and its concentration in body fluids and in endometrial tissues of mares.

Pharmacokinetics and distribution of orbifloxacin into body fluids and endometrium was studied in 6 mares after intragastric (IG) administration at a single dose rate of 7.5 mg/kg body weight. Orbifloxacin concentrations were serially measured in serum, synovial fluid, peritoneal fluid, urine, cerebrospinal fluid, and endometrial tissues over 24 hours. Minimum inhibitory concentrations of orbifloxacin were determined for 120 equine pathogens over an 11-month period. The mean peak serum concentration (Cmax) was 2.41+/-0.30 microg/mL at 1.5 hours after administration and decreased to 0.17+/-0.01 microg/mL (Cmin) at 24 hours. The mean elimination half-life (t1/2) was 9.06+/-1.33 hours and area under the serum concentration vs time curve (AUC) was 20.54+/-1.70 mg h/L. Highest mean peritoneal fluid concentration was 2.15+/-0.49 microg/mL at 2 hours. Highest mean synovial fluid concentration was 1.17+/-0.28 microg/mL at 4 hours. Highest mean urine concentration was 536.67+/-244.79 microg/mL at 2 hours. Highest mean endometrial concentration was 0.72+/-0.23 microg/g at 1.5 hours. Mean CSF concentration was 0.46+/-0.55 microg/mL at 3 hours. The minimum inhibitory concentration of orbifloxacin required to inhibit 90% of isolates (MIC90) ranged from < or = 0.12 to > 8.0 microg/mL, with gram-negative organisms being more sensitive than gram-positive organisms. Orbifloxacin was uniformly absorbed in the 6 mares and was well distributed into body fluids and endometrial tissue. At a dosage of 7.5 mg/kg once a day, many gram-negative pathogens, such as Actinobacillus equuli, Escherichia coli, Pasteurella spp., and Salmonella spp. would be expected to be susceptible to orbifloxacin.