Enantiospecific pharmacokinetics of ketoprofen in plasma and synovial fluid of horses with acute synovitis

Pharmacokinetic parameters were established for enantiomers of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (KTP) administered as the racemic mixture at a dose of 2.2 mg/kg and as separate enantiomers, each at a dose of 1.1 mg/kg to a group of six horses (five mares and one gelding). A four-period cross-over study in a LPS-induced model of acute synovitis was used. After administration of the racemic mixture S(+)KTP was the predominant enantiomer in plasma as well as in synovial fluid. Unidirectional inversion of R(-) to S(+)KTP was demonstrated but the inversion was less marked than previously reported. It is suggested that this reduction could be because of the influence of the inflammatory reaction on hepatic metabolism. The disposition of KTP enantiomers after administration of the racemic mixture was similar to those observed after administration of S(+) and R(-)KTP. The S(+) and R(-)KTP concentrations in synovial fluid were low and short lasting. After administration of R(-)KTP significant concentrations of the optical antipode were detected in synovial fluid.     

Oral bioavailability and pharmacokinetic characteristics of ketoprofen enantiomers after oral and intravenous administration in Asian elephants (Elephas maximus)

OBJECTIVE: To assess oral bioavailability (F) and pharmacokinetic characteristics of the R- and S-enantiomers of ketoprofen administered IV and orally to captive Asian elephants (Elephas maximus). ANIMALS: 5 adult Asian elephants. PROCEDURE: Elephants received single treatments of racemic ketoprofen at a dose of 2.2 mg/kg, administered IV and orally, in a complete crossover design. Blood samples were collected at intervals during the 24 hours following treatment. At least 4 weeks elapsed between drug administrations. Samples were analyzed for R- and S-ketoprofen with a validated liquid chromatography-mass spectroscopic assay. Pharmacokinetic parameters were determined by use of noncompartmental analysis. RESULTS: The enantiomers of ketoprofen were absorbed well after oral administration, with median F of 101% for R-ketoprofen and 85% for S-ketoprofen. Harmonic mean half-life ranged from 3.8 to 5.5 hours, depending on route of administration and enantiomer. The area under the concentration-time curve, mean residence time, apparent volume of distribution, plasma clearance, and maximum plasma concentration values were all significantly different between the 2 enantiomers for both routes of administration. CONCLUSIONS AND CLINICAL RELEVANCE: Ketoprofen has a long terminal half-life and complete absorption in this species. Based on the pharmacokinetic data, a dosage of ketoprofen of 1 mg/kg every 48 hours to 2 mg/kg every 24 hours, PO or IV, is recommended for use in Asian elephants, although the safety and efficacy of ketoprofen during long-term administration in elephants have not been determined.     

Pharmacokinetics of intravenous and intragastric cimetidine in horses I. Effects of intravenous cimetidine on pharmacokinetics of intravenous phenylbutazone

Cimetidine was administered intravenously and by the intragastric route to six mares at a dose of 4.0 mg/kg of body weight (bw). Specific and sensitive high performance liquid chromatographic methods for the determination of cimetidine in horse plasma and urine and cimetidine sulfoxide in urine are described. Plasma cimetidine concentration vs. time data were analysed by non-linear least squares regression analysis to determine pharmacokinetic parameter estimates. The median (range) plasma clearance (Cl) was 8.20 (4.96–10.2) mL/min.kg of body weight, that of the steady-state volume of distribution (Vd_ss) was 0.771 (0.521–1.15) L/kg bw, and that of the terminal elimination half-life ( t _½β) was 92.4 (70.6–125) minutes. The median (range) renal clearance of cimetidine was 4.08 (2.19–6.23) mL/min.kg bw or 55.4 (36.3–81.8)% of the corresponding plasma clearance. Cimetidine sulfoxide was excreted in urine and its urinary excretion through 8 h accounted for 12.0 (9.8–16.6)% of the plasma clearance of cimetidine. The median (range) extent of intragastric bioavailability was 14.4 (6.82–21.8)% and the maximum plasma concentration after intragastric administration was 0.31 (0.24–0.50) μg/mL.
Intravenous cimetidine had no effect on the disposition of intravenous phenylbutazone or its metabolites except that the maximum plasma concentration of γ-hydroxyphenylbutazone was less after cimetidine treatment.     

Pharmacokinetics of probenecid and the effect of oral probenecid administration on the pharmacokinetics of cefazolin in mares

The pharmacokinetics and bioavailability of probenecid given IV and orally at the dosage level of 10 mg/kg of body weight to mares were investigated. Probenecid given IV was characterized by a rapid disposition phase with a mean half-life of 14.0 minutes and a subsequent slower elimination phase with a mean half-life of 87.8 minutes in 5 of 6 mares. In the remaining mare, a rapid disposition phase was not observed, and the half-life of the elimination phase was slower (172 minutes). The mean residence time of probenecid averaged 116 minutes for all 6 mares and 89.2 minutes for the 5 mares with biphasic disposition. The total plasma clearance of probenecid averaged 1.18 +/- 0.49 ml/min/kg, whereas renal clearance accounted for 42.6 +/- 9.3% of the total clearance. The steady-state volume of distribution of probenecid averaged 116 +/- 28.2 ml/kg. Plasma protein binding of probenecid was extensive, with 99.9% of the drug bound at plasma probenecid concentrations of 10 micrograms/ml. The maximum plasma probenecid concentration after 10 mg/kg orally averaged nearly 30 micrograms/ml. The half-life of probenecid after oral administration was approximately 120 minutes. Oral bioavailability was good with greater than 90% of the dose absorbed. The effect of probenecid on tubular secretion of organic anions was evaluated by determining the pharmacokinetics of IV cefazolin (11 mg/kg) administered alone and 15 minutes after probenecid (10 mg/kg orally). Treatment with probenecid did not affect pharmacokinetic values of cefazolin. This failure of probenecid to alter the pharmacokinetics of cefazolin may be caused by insufficient plasma probenecid concentrations after the oral dose.     

Pharmacokinetics and synovial fluid concentrations of flurbiprofen enantiomers in horses: chiral inversion

Flurbirpofen (FBP), a member of the 2-aryl propionate nonsteroidal anti-inflammatory drug class, has potent anti-inflammatory and analgesic properties. The commercial preparation is a racemic mixture of the R(-) and S(+) enantiomers of FBP. In this study, R(-) and S(+) FBP were used to investigate the metabolic chiral inversion. Each enantiomer was administered separately (0.25 mg/kg) and in a racemic mixture (0.5 mg/kg) intravenously to horses. Plasma and synovial concentration of each enantiomer was determined and the disposition of each was analyzed. After intravenous administration of R(-) FBP and S(+) FBP to horses no chiral inversion was detected. After the administration of the FBP racemate and individual enantiomers no differences were observed between pharmacokinetic parameters [t(1/2beta) (h), Cl (L/h.kg), AUC (microg.h/mL), Vss (L/kg) and MRT (h)] for R(-) and S(+) FBF. Synovial fluid concentrations of both FBP enantiomers were lower than plasma concentrations and no stereoselective differences were detected. These data indicate that the disposition of FBF in horses is not enantioselective and demonstrate a difference in the pharmacokinetic behavior of the enantiomers as compared with other 2-aryl-propionic acids, such as carprofen, ketoprofen and vedaprofen in the horse.     

Pharmacokinetics of the antihyperglycemic agent metformin in cats.

OBJECTIVE: To determine the pharmacokinetics of metformin in healthy cats after single-dose IV and oral administration of the drug. ANIMALS: 6 healthy adult ovariohysterectomized cats. PROCEDURE: In a randomized cross-over design study, each cat was given 25 mg of metformin/kg of body weight, IV and orally. Blood and urine samples were collected after drug administration, and concentrations of metformin in plasma and urine were determined by use of high-performance liquid chromatography. RESULTS: Disposition of the drug was characterized by a three-compartment model with a terminal phase half-life of (mean +/- SD) 11.5+/-4.2 hours. Metformin was distributed to a small central compartment of 0.057+/-0.017 L/kg and to 2 peripheral compartments with volumes of distribution of 0.12+/-0.02 and 0.37+/-0.38 L/kg. Steady-state volume of distribution was 0.55+/-0.38 L/kg. After IV administration, 84+/-14% of the dose was excreted unchanged in urine, with renal clearance of 0.13+/-0.03 L/h/kg; nonrenal clearance was negligible (0.02+/-0.02 L/kg). Mean bioavailability of orally administered metformin was 48%. CONCLUSIONS: The general disposition pattern of metformin in cats is similar to that reported for humans. Metformin was eliminated principally by renal clearance; therefore, this drug should not be used in cats with substantial renal dysfunction. CLINICAL RELEVANCE: On the basis of our results, computer simulations indicate that 2 mg of metformin/kg administered orally every 12 hours to cats will yield plasma concentrations documented to be effective in humans.     

Pharmacokinetic studies of cimetidine hydrochloride in adult horses

Histamine type II (H2) antagonists inhibit gastric acid secretion and are useful in treating gastric and duodenal ulcer disease. To provide some information on the pharmacokinetics of the H2 antagonist cimetidine, adult horses were given 3.3 mg/kg cimetidine intravenously (iv) or 3.3 and 10 mg/kg orally. Plasma cimetidine concentrations after 3.3 mg/kg orally were too low to measure. Following 3.3 mg/kg iv, cimetidine displayed two-compartment characteristics with a t1/2 of 0.083 +/- 0.039 h and t1/2 of 2.23 +/- 0.64 h. The total body clearance was 0.443 +/- 0.160 litre/h/kg and the mean residence time was 2.74 +/- 1.11 h. This clearance and t1/2 are similar to that in man. The volume of distribution (Vss) and volume of the central compartment (Vc) were 1.138 +/- 0.230 and 0.276 +/- 0.102 litre/kg, respectively. After a single oral dose of 10 mg/kg as crushed tablets, peak plasma concentration of 1.81 +/- 0.82 micrograms/ml occurred at approximately 1.4 h. Oral absorption of cimetidine appeared variable and slow with an extent of absorption of 0.296 +/- 0.183 and a mean residence time for absorption of 1.99 +/- 0.79 h. This was less than in man. Based on a desired average steady state plasma concentration of 1.0 microgram/ml, 11.0 mg/kg/day iv and 48 mg/kg/day orally can be recommended in adult horses.     

Disposition of suprofen enantiomers in the cat.

Suprofen (SPF) is a non-steroidal anti-inflammatory drug (NSAID), which belongs to the 2-arylpropionic acids subclass. As a result of their chiral characteristics, these compounds have shown a marked enantioselective behaviour with a high degree of interspecies variation. They are mainly eliminated by glucuronidation. Plasma, biliary and urine disposition of SPF was investigated in the cat after intravenous administration of the racemate (dose 2 mg/kg). Both enantiomers exhibited similar disposition profiles in plasma with no evidence of chiral inversion. During bile sampling time, recovered acylglucuronides of R (-) and S (+) SPF were less than 1% of the total dose administered. Only free SPF was recovered in the urine, representing 0.12% of the administered racemic SPF dose. The results indicate that neither chiral inversion nor glucuronidation predominate in SPF disposition in cats. Copyright Harcourt Publishers Ltd.     

Pharmacokinetics of the insulin-sensitizing agent troglitazone in cats

OBJECTIVE: To determine pharmacokinetics of troglitazone in healthy cats after i.v. and oral administration of a single dose of the drug. ANIMALS: 5 healthy ovariohysterectomized adult cats. PROCEDURE: Using a randomized crossover design, cats were given 5 mg of troglitazone/kg of body weight i.v. and 40 mg of troglitazone/kg orally. Blood and urine samples were collected after drug administration, and concentrations of troglitazone in plasma and urine were determined by use of high-performance liquid chromatography. RESULTS: Area-moment analysis was used to calculate pharmacokinetic variables. Terminal phase half-life was 1.1 +/- 0.1 hours. Steady-state volume of distribution was 0.23 +/- 0.15 L/kg. After i.v. administration, clearance was 0.33 +/- 0.04 L/h/kg. Drug was not detected in urine samples. Mean bioavailability of orally administered troglitazone was 6.9%. CONCLUSIONS AND CLINICAL RELEVANCE: The overall disposition of troglitazone in cats was similar to that reported in other species, including humans. Troglitazone has low and variable oral bioavailability. Clearance of the compound is moderate. Little if any unchanged troglitazone is excreted in urine; thus, metabolism and biliary excretion play predominant roles in elimination of the drug. On the basis of troglitazone pharmacokinetics in healthy cats, as well as on the basis of pharmacodynamics of the drug in humans and other animals, a regimen that uses a dosage of 20 to 40 mg/kg administered orally once or twice per day to cats will produce plasma concentrations of the insulin-sensitizing agent that have been documented to be effective in humans.     

Species comparison of enantioselective oral bioavailability and pharmacokinetics of ketoprofen

As a part of ongoing research to further elucidate frequent and species-specific causes of differences in oral bioavailability, a 3 mg/kg dose of racemic ketoprofen, a high permeability/low solubility compound in the human biopharmaceutics classification system, was administered intravenously and orally to different species. Due to possible enantioselective disposition kinetics and inversion, enantiomers were quantitated separately using a stereospecific HPLC assay. The absolute bioavailability of R(−) and S(+) ketoprofen in chickens, turkeys, dogs and pigs was 31.5% and 52.6%, 42.6% and 32.5%, 33.6% and 89.1%, and 85.9% and 83.5% respectively. Incomplete bioavailability in poultry is probably due to incomplete absorption in addition to first-pass elimination. Low bioavailability of R(−) ketoprofen in dogs, strongly indicates first-pass metabolism. High bioavailability of S(+) ketoprofen in dogs and both enantiomers in pigs confirms that absorption of these substances is complete and controlled by gastric emptying rather than dissolution.     

Species comparison of enantioselective oral bioavailability and pharmacokinetics of ketoprofen

As a part of ongoing research to further elucidate frequent and species-specific causes of differences in oral bioavailability, a 3 mg/kg dose of racemic ketoprofen, a high permeability/low solubility compound in the human biopharmaceutics classification system, was administered intravenously and orally to different species. Due to possible enantioselective disposition kinetics and inversion, enantiomers were quantitated separately using a stereospecific HPLC assay. The absolute bioavailability of R(−) and S(+) ketoprofen in chickens, turkeys, dogs and pigs was 31.5% and 52.6%, 42.6% and 32.5%, 33.6% and 89.1%, and 85.9% and 83.5% respectively. Incomplete bioavailability in poultry is probably due to incomplete absorption in addition to first-pass elimination. Low bioavailability of R(−) ketoprofen in dogs, strongly indicates first-pass metabolism. High bioavailability of S(+) ketoprofen in dogs and both enantiomers in pigs confirms that absorption of these substances is complete and controlled by gastric emptying rather than dissolution.     

Estimation of absolute oral bioavailability of moxidectin in dogs using a semi-simultaneous method: influence of lipid co-administration

Moxidectin is a long-acting anthelmintic drug for which little is known about its kinetic behaviour in dogs and its oral absolute bioavailability has never been reported. We studied the pharmacokinetics of moxidectin in dogs, with a special emphasis on oral bioavailability and the influence of lipid co-administration, by using a semi-simultaneous method of administration. Ten Beagle dogs were dosed orally and then intravenously (i.v.) with 0.2 mg/kg moxidectin. The oral application was conducted with or without corn oil co-administration. Moxidectin concentration-time profiles in plasma were analysed using a compartmental modelling approach, designed to fit the oral and i.v. kinetic disposition curves simultaneously. In contrast to what happens in other species, our study indicates that the bioavailability of orally given moxidectin in dogs is nearly total (90.2 +/- 7.4%), and is not enhanced by lipid co-administration. The clearance, the volume of distribution, the mean residence time and the terminal half-life were similar to what was already described for other species. Finally our trial suggests that the body condition (degree of obesity) is likely to be a major determinant of moxidectin kinetics in dogs because of its modulation of the volume of distribution that indirectly controls the terminal half-life of the drug.     

Pharmacokinetics of fluconazole after oral administration of single and multiple doses in African grey parrots

OBJECTIVE: To determine the pharmacokinetics and effects of orally administered fluconazole in African grey parrots. ANIMALS: 40 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). PROCEDURE: In single-dose trials, parrots were placed into groups of 4 to 5 birds each and fluconazole was administered orally at 10 and 20 mg/kg. Blood samples for determination of plasma fluconazole concentrations were collected from each group at 2 or 3 of the following time points: 1, 3, 6, 9, 12, 24, 31, 48, and 72 hours. In multiple-dose trials, fluconazole was administered orally to groups of 5 birds each at doses of 10 and 20 mg/kg every 48 hours for 12 days. Trough plasma concentrations were measured 3 times during treatment. Groups receiving 20 mg/kg were monitored for changes in plasma biochemical analytes, and blood samples were collected on days 1 and 13 of treatment to allow comparison of terminal half-life. RESULTS: Peak plasma concentrations of fluconazole were 7.45 and 18.59 microg/mL, and elimination half-lives were 9.22 and 10.19 hours for oral administration of 10 and 20 mg/kg, respectively. Oral administration of fluconazole for 12 days at 10 or 20 mg/kg every 48 hours did not cause identifiable adverse effects or change the disposition of fluconazole. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of fluconazole to parrots at 10 to 20 mg/kg every 24 to 48 hours maintains plasma concentrations above the minimum inhibitory concentration for several common yeast species. The prolonged dosing interval is an advantage of this treatment regimen.     

The oral bioavailability of ibuprofen enantiomers in broiler chickens

Doses of racemic ibuprofen ranging from 5 to 20 mg/kg body weight were administered intravenously (i.v.) and orally to broiler chickens and plasma concentration-time profiles for both ibuprofen enantiomers were determined. The absorption of ibuprofen was evaluated after a bolus administration of a commercially available suspension into the crop and proventriculus, respectively. An enterohepatic circulation as described for other nonsteroidal anti-inflammatory drugs (NSAIDs) in other species could be suggested for both enantiomers after i.v. and oral administration. Significantly higher area under the curve (AUC) values for S(+)-ibuprofen compared with R(-)-ibuprofen were collected after crop and proventriculus administration. Several factors could be responsible for the significant differences in AUC values between both enantiomers.     

Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep

Pharmacokinetic and pharmacodynamic parameters were established for the enantiomers of the 2-arylpropionic acid (APA) nonsteroidal anti-inflammatory drug (NSAID), ketoprofen (KTP). Each enantiomer was administered separately (1.5 mg/kg) and in a racemic mixture (3 mg/kg) intravenously (i.v.) to a group of eight sheep in a four-way, four-period cross-over study using a tissue cage model of inflammation. Plasma disposition of each KTP enantiomer was similar following separate administration of the pure compounds compared to administration of the racemic mixture. S(+)KTP volume of distribution (Vd(area)) was higher and clearance (ClB) faster than those of R(-)KTP. S(+) and R(-)KTP achieved relatively low concentrations in exudate and transudate. Unidirectional limited chiral inversion of R(-) to S(+)KTP was demonstrated. After R(-)KTP administration S(+)KTP was detected in plasma, but not in either exudate or transudate. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(-)KTP administration because of chiral inversion to S(+)KTP, but the pharmacodynamic parameters, calculated maximum effect (Emax), concentration producing 50% effect (EC50), Hill's coefficient (N), rate constant of elimination of drug effect from the compartment (KeO) and mean equilibration half-life (t1/2KeO) were determined for S(+)KTP after administration of the racemic mixture as well as the pure compound.     

Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets

Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment ( t _max = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed ( t _max = 2.25 h) and decreased the rate and extent of absorption ( AUC ) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.     

Comparative plasma disposition of fenbendazole, oxfendazole and albendazole in dogs

The plasma disposition of fenbendazole (FBZ), oxfendazole (OFZ) and albendazole (ABZ); and the enantiospecific disposition of OFZ, and ABZSO produced were investigated following an oral administration (50 mg/kg) in dogs. Blood samples were collected from 1 to 120 h post-administration. The plasma samples were analysed by high performance liquid chromatography (HPLC). The plasma concentration of FBZ, OFZ, ABZ and their metabolites were significantly different from each other and depended on the drug administered. The sulphone metabolite (FBZSO2) of FBZ was not detected in any plasma samples and the parent molecule ABZ did not reach quantifiable concentrations following FBZ and ABZ administration, respectively. OFZ and its sulphone metabolite attained a significantly higher plasma concentration and remained much longer in plasma compared with FBZ and ABZ and their respective metabolites. The maximum plasma concentrations (Cmax), area under the concentration time curve (AUC) and mean residence time (MRT) of parent OFZ were more than 30, 68 and 2 times those of FBZ, respectively. The same parameters for ABZSO were also significantly greater than those of FBZSO. The ratio for total AUCs of both the parent drug and the metabolites were 1:42:7 for following FBZ, OFZ and ABZ administration, respectively. The enantiomers were never in racemic proportions and (+) enantiomers of both OFZ and ABZSO were predominant in plasma. The AUC of (+) enantiomers of OFZ and ABZSO was, respectively more than three and seven times larger than that of (-) enantiomers of both molecules. It is concluded that the plasma concentration of OFZ was substantially greater compared with FBZ and ABZ. The data on the pharmacokinetic profile of OFZ presented here may contribute to evaluate its potential as an anthelmintic drug for parasite control in dogs.     

Involvement of P-glycoprotein on ivermectin kinetic behaviour in sheep: itraconazole-mediated changes on gastrointestinal disposition

Different pharmacological approaches have been used in an attempt to increase the systemic availability of anthelmintic drugs. The comparative effect of the itraconazole (ITZ)-mediated modulation of P-glycoprotein (P-gp) activity on the in vivo kinetic behaviour of ivermectin (IVM) administered by the intravenous (i.v.) and intraruminal (i.r.) routes to sheep was assessed in the current work. Corriedale sheep received IVM (50 microg/kg) by the i.v. route either alone (group A) or co-administered with the P-gp modulator ITZ (100 mg orally three times every 12 h) (group B). Animals in groups C and D were intraruminally treated with IVM (50 microg/kg) alone or co-administered with ITZ (100 mg orally three times every 12 h) respectively. Jugular blood and gastrointestinal tissue samples (animals treated by the i.r. route) were collected. The samples were analysed by HPLC using fluorescence detection. The plasma disposition of IVM given intravenously was unaffected by the presence of ITZ. However, after the i.r. treatment the co-administration with ITZ resulted in markedly higher IVM plasma concentration profiles compared to the control group. Likewise, the presence of ITZ enhanced the IVM concentration profiles measured in the gastrointestinal mucosal tissues. An ITZ-induced reduction on the P-gp efflux activity at the intestinal lining may have accounted for the greater absorption and enhanced systemic availability observed for IVM in the intraruminally treated animals.     

Effect of enrofloxacin on digoxin clearance and steady-state serum concentrations in dogs.

The effect of enrofloxacin on the oral clearance and steady-state concentrations of digoxin in serum was evaluated in dogs. Digoxin was administered orally to six healthy adult Beagle dogs following a multiple-dose regimen of 0.0625 mg every 12 h for 23 days. From days 14 to 23 enrofloxacin was administered orally at a dosage of 2.5 mg/kg every 12 h, with subjects receiving enrofloxacin 2 h prior to digoxin. Trough serum concentrations of digoxin were measured using an immunoassay technique. On days 13 and 22, dogs were catheterized for multiple blood sample collection during the 12 h digoxin dosing interval and serum samples were analyzed for digoxin concentrations. In general, steady-state digoxin concentrations in trough serum were not significantly different during enrofloxacin treatment than before enrofloxacin administration. Similarly, digoxin oral clearance was not significantly different between pre-enrofloxacin and digoxin + enrofloxacin periods. We conclude that enrofloxacin is unlikely to have a significant impact on digoxin disposition in dogs.     

Pharmacokinetics and bioavailability of cephalothin in horse mares

The pharmacokinetics and bioavailability of cephalothin given to 6 horse mares at a dosage level of 11 mg/kg of body weight IV or IM were investigated. The disposition of cephalothin given IV was characterized by a rapid disposition phase with a mean half-life of 2.89 minutes and a subsequent slower elimination phase with a mean half-life of only 14.7 minutes. The mean residence time of cephalothin was 10.6 +/- 2.11 minutes. The total plasma clearance of cephalothin averaged 13.6 ml/min/kg and was caused by metabolism and renal elimination. Renal clearance of cephalothin averaged 1.32 ml/min/kg and accounted for elimination of about 10.1% of the administered dose. The volume of distribution at steady state averaged 151 mg/kg. Plasma protein binding of cephalothin at a concentration of 10 micrograms/ml averaged 17.9 +/- 2.5%. Cephalothin was rapidly metabolized to desacetylcephalothin. Maximum plasma desacetylcephalothin concentrations were observed in the blood samples collected 5 minutes after IV doses and averaged 22.9 micrograms/ml. The apparent half-life of desacetylcephalothin in plasma was 41.6 minutes and its renal clearance averaged 4.49 +/- 2.43 ml/min/kg. An average of 33.9% of the dose was recovered in the urine as desacetylcephalothin. The maximum plasma cephalothin concentration after IM administration was 11.3 +/- 3.71 micrograms/ml. The terminal half-life was 47.0 minutes and was longer than the half-life after IV administration. The bioavailability of cephalothin given IM ranged from 38.3% to 93.1% and averaged 65.0 +/- 20.5%.