Disposition, bioavailability and clinical efficacy of orally administered acepromazine in the horse

The pharmacokinetics and pharmacological efficacy of orally (p.o.) administered acepromazine were studied and compared with the intravenous (i.v.) route of administration in a cross-over study using six horses. The oral kinetics of acepromazine can be described by a two-compartment open model with first-order absorption. The drug was rapidly absorbed after p.o. administration with a half-life of 0.84 h, t _max of 0.4 h and C _max of 59 ng/ml. The elimination was slower after p.o. administration (half-life 6.04 h) than after i.v. injection (half-life 2.6 h). The bioavailability of the orally administered drug formulation was 55.1%. After p.o. administration of 0.5 mg/kg acepromazine, the parameters of the sedative effect were similar to those obtained after i.v. injection of 0.1 mg/kg. The effect of the drug on blood cell count and haemoglobin content was similar after both p.o. administration and injection, while the effects on the parameters of penile prolapse and on the mean arterial blood pressure were less pronounced after p.o. administration than after injection. After p.o. administration, no significant effects on haematoerit-level as well as on the heart and respiratory rates were observed, while these parameters were significantly affected after injection. It is concluded that the high initial plasma level of the drug after i.v. injection may play a role in producing adverse effects of acepromazine.     

Pharmacokinetics of azathioprine following single-dose intravenous and oral administration and effects of azathioprine following chronic oral administration in horses

OBJECTIVE: To determine pharmacokinetics of azathioprine (AZA) and clinical, hematologic, and serologic effects of i.v. and oral administration of AZA in horses. ANIMALS: 6 horses. PROCEDURE: In study phase 1, a single dose of AZA was administered i.v. (1.5 mg/kg) or orally (3.0 mg/kg) to 6 horses, with at least 1 week between treatments. Blood samples were collected for AZA and 6-mercaptopurine (6-MP) analysis 1 hour before and at predetermined time points up to 4 hours after AZA administration. In study phase 2, AZA was administered orally (3 mg/kg) every 24 hours for 30 days and then every 48 hours for 30 days. Throughout study phase 2, blood samples were collected for CBC determination and serum biochemical analysis. RESULTS: Plasma concentrations of AZA and its metabolite, 6-MP decreased rapidly from plasma following i.v. administration of AZA, consistent with the short mean elimination half-life of 1.8 minutes. Oral bioavailability of AZA was low, ranging from 1% to 7%. No horses had abnormalities on CBC determination or serum biochemical analysis, other than 1 horse that was lymphopenic on day 5 and 26 of daily treatment. This horse developed facial alopecia from which 1 colony of a Trichophyton sp was cultured; alopecia resolved within 1 month after the study ended. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, no adverse effects were observed with long-term oral administration of AZA to horses, although 1 horse did have possible evidence of immunosuppression with chronic treatment. Further investigation of the clinical efficacy of AZA in the treatment of autoimmune diseases in horses is warranted.     

Cardiorespiratory and metabolic effects of xylazine, detomidine, and a combination of xylazine and acepromazine administered after exercise in horses

OBJECTIVE: To determine sedative, cardiorespiratory and metabolic effects of xylazine hydrochloride, detomidine hydrochloride, and a combination of xylazine and acepromazine administered i.v. at twice the standard doses in Thoroughbred horses recuperating from a brief period of maximal exercise. ANIMALS: 6 adult Thoroughbreds. PROCEDURE: Horses were preconditioned by exercising them on a treadmill to establish a uniform level of fitness. Each horse ran 4 simulated races, with a minimum of 14 days between races. Simulated races were run at a treadmill speed that caused horses to exercise at 120% of their maximal oxygen consumption. Horses ran until they were fatigued or for a maximum of 2 minutes. One minute after the end of exercise, horses were treated i.v. with xylazine (2.2 mg/kg of body weight), detomidine (0.04 mg/kg), a combination of xylazine (2.2 mg/kg) and acepromazine (0.04 mg/kg), or saline (0.9% NaCl) solution. Treatments were randomized so that each horse received each treatment once, in random order. Cardiopulmonary indices were measured, and samples of arterial and venous blood were collected immediately before and at specific times for 90 minutes after the end of each race. RESULTS: All sedatives produced effective sedation. The cardiopulmonary depression that was induced was qualitatively similar to that induced by administration of these sedatives to resting horses and was not severe. Sedative administration after exercise prolonged the exercise-induced increase in body temperature. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of xylazine, detomidine, or a combination of xylazine-acepromazine at twice the standard doses produced safe and effective sedation in horses that had just undergone a brief, intense bout of exercise.     

Pharmacokinetics of thiopentone in the horse

Abass, B.T., Weaver, B.M.Q., Staddon, G.E., Waterman, A.W. Pharmacokinetics of thiopentone in the horse. J. vet. Pharmacol. Therap . 17 , 331–338.
The pharmacokinetics of thiopentone sodium administered intravenously as a single dose (11 mg/kg) were studied in acepromazine pre-medicated horses and ponies in which anaesthesia was maintained with either halothane (Group 1) or isoflurane (Group 2). The results showed that the disposition kinetics of thiopentone in horses and ponies were best described by a three-compartment open model. In plasma, a very short initial distribution phase in both horses and ponies, half-life 1.4 ± 1.2 min (mean ± SD) and 1.3 ± 0.7 min, respectively, was obtained, which was followed by a second comparatively slower redistribution phase, half-life 16 ± 12 min and 11 ± 5 min, respectively. The volume of distribution for the drug was large, especially in the ponies which received isoflurane (1127 ± 86 ml/kg). compared to the horses which received halothane (742 ± 89 ml/kg). The drug had a somewhat shorter elimination half-life in the horses (147 ± 21 min) than in the ponies (222 ± 44 min), but no obvious difference in clearance of the drug was observed between the horses (3.5 ± 0.5 ml/min/kg) and ponies (3.6 ± 0.8 ml/min/kg).     

Pharmacokinetics and tissue fluid distribution of cephalexin in the horse after oral and i.v. administration

The purpose of this study was to determine the pharmacokinetics and tissue fluid distribution of cephalexin in the adult horse following oral and i.v. administration. Cephalexin hydrate (10 mg/kg) was administered to horses i.v. and plasma samples were collected. Following a washout period, cephalexin (30 mg/kg) was administered intragastrically. Plasma, interstitial fluid (ISF) aqueous humor, and urine samples were collected. All samples were analyzed by high-pressure liquid chromatography (HPLC). Following i.v. administration, cephalexin had a plasma half-life (t(1/2)) of 2.02 h and volume of distribution [V(d(ss))] of 0.25 L/kg. Following oral administration, the average maximum plasma concentration (C(max)) was 3.47 mug/mL and an apparent half-life (t(1/2)) of 1.64 h. Bioavailability was approximately 5.0%. The AUC(ISF):AUC(plasma) ratio was 80.55% which corresponded to the percentage protein-unbound drug in the plasma (77.07%). The t(1/2) in the ISF was 2.49 h. Cephalexin was not detected in the aqueous humor. The octanol:water partition coefficient was 0.076 +/- 0.025. Cephalexin was concentrated in the urine with an average concentration of 47.59 microg/mL. No adverse events were noted during this study. This study showed that cephalexin at a dose of 30 mg/kg administered orally at 8 h dosage intervals in horses can produce plasma and interstitial fluid drug concentrations that are in a range recommended to treat susceptible gram-positive bacteria (MIC < or = 0.5 microg/mL). Because of the low oral bioavailability of cephalexin in the horse, the effect of chronic dosing on the normal intestinal bacterial flora requires further investigation.     

Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally infected with influenza virus A2.

OBJECTIVE: To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg, p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus. RESULTS: Estimated mean peak plasma concentration of rimantadine after i.v. administration was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/- 7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half-life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection.     

Clinical pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate after oral administration in horses

The aim of this study was to investigate the pharmacokinetics of oseltamivir carboxylate (OC) in horses (n=6) after oral administration of its prodrug oseltamivir. The binding rate of OC to horse plasma proteins was negligible (<1%). Oral administration of oseltamivir of 2 mg/kg body weight of oseltamivir to horses provided a plasma concentration of OC (mean maximum concentration: 257.9 ng/ml) above the inhibitory concentrations against equine influenza A viruses determined in vitro. However, because OC is rapidly eliminated from horse plasma (mean elimination half-life: 2.5 hr), administration intervals should be less than 10 hr to retain a suitable concentration when using a single dose of 2 mg/kg oseltamivir.     

Influence of general anaesthesia on the pharmacokinetics of intravenous fentanyl and its primary metabolite in horses

REASONS FOR PERFORMING STUDY: In order to evaluate its potential as an adjunct to inhalant anaesthesia in horses, the pharmacokinetics of fentanyl must first be determined. OBJECTIVES: To describe the pharmacokinetics of fentanyl and its metabolite, N-[1-(2-phenethyl-4-piperidinyl)maloanilinic acid (PMA), after i.v. administration of a single dose to horses that were awake in Treatment 1 and anaesthetised with isoflurane in Treatment 2. METHODS: A balanced crossover design was used (n = 4/group). During Treatment 1, horses received a single dose of fentanyl (4 microg/kg bwt, i.v.) and during Treatment 2, they were anaesthetised with isoflurane and maintained at 1.2 x minimum alveolar anaesthetic concentration. After a 30 min equilibration period, a single dose of fentanyl (4 microg/kg bwt, i.v.) was administered to each horse. Plasma fentanyl and PMA concentrations were measured at various time points using liquid chromatography-mass spectrometry. RESULTS: Anaesthesia with isoflurane significantly decreased mean fentanyl clearance (P < 0.05). The fentanyl elimination half-life, in awake and anaesthetised horses, was 1 h and volume of distribution at steady state was 0.37 and 0.26 l/kg bwt, respectively. Anaesthesia with isoflurane also significantly decreased PMA apparent clearance and volume of distribution. The elimination half-life of PMA was 2 and 1.5 h in awake and anaesthetised horses, respectively. CONCLUSIONS AND POTENTIAL RELEVANCE: Pharmacokinetics of fentanyl and PMA in horses were substantially altered in horses anaesthetised with isoflurane. These pharmacokinetic parameters provide information necessary for determination of suitable fentanyl loading and infusion doses in awake and isoflurane-anaesthetised horses.     

Drug disposition and dosage determination of once daily administration of gentamicin sulfate in horses after abdominal surgery.

OBJECTIVE: To evaluate pharmacokinetics of once daily i.v. administration of gentamicin sulfate to adult horses that had abdominal surgery. DESIGN: Prospective study. ANIMALS: 28 adult horses that underwent abdominal surgery for colic. PROCEDURE: 14 horses were treated with each dosage of gentamicin (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) and blood samples were collected for pharmacokinetic analysis. Plasma gentamicin concentrations were measured by use of a fluorescence polarization immunoassay. Pharmacokinetic analysis measured the elimination half-life, volume of distribution, and gentamicin total systemic clearance. Treatment outcome, CBC, and serum creatinine concentrations were recorded. RESULTS: 1 horse in the high-dosage group died. All other horses successfully recovered, and did not develop bacterial infection or have evidence of drug toxicosis resulting in renal injury. Mean pharmacokinetic variables for gentamicin administration at a high or low dosage (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) were half-life of 1.47 and 1.61 hours, volume of distribution of 0.17 and 0.17 L/kg, and systemic clearance of 1.27 and 1.2 ml/kg/min, respectively. Mean serum creatinine concentration was 1.74 and 1.71 for the high and low dosages, respectively, and serum creatinine concentration was not correlated with gentamicin clearance. CONCLUSIONS AND CLINICAL RELEVANCE: Gentamicin administration at a dosage of 4 mg/kg, i.v., every 24 hours, will result in plasma concentrations that are adequate against susceptible bacteria with a minimum inhibitory concentration (MIC) of < or = 2.0 micrograms/ml. Gentamicin administration at a calculated dosage of 6.8 mg/kg, i.v., every 24 hours will result in optimum plasma concentrations against susceptible bacteria with a MIC of < or = 4.0 micrograms/ml.     

Pharmacokinetics of phenolsulfonphthalein in horse and pony mares

Pharmacokinetics of phenolsulfonphthalein (PSP) in horse and pony mares was determined after injection of 1 mg/kg of body weight, IV. A plasma PSP concentration vs time curve was described adequately in horses and ponies by an open, 2-compartment model. There were significant differences in the elimination phase parameters, apparent volume of distribution at steady state, and apparent volume of distribution of horses and ponies. The harmonic mean elimination half-life of PSP in horses was significantly longer (P less than 0.001) than that in the ponies (16.4 and 10.0 minutes, respectively). The mean plasma clearance of PSP in horses was significantly (P less than 0.05) less than that in ponies (0.00554 and 0.00701 L/min/kg, respectively). There was no difference between horses and ponies in the metabolic clearance of PSP. The fraction of the administered dose of PSP excreted in the urine in the first 15 minutes was not significantly different between horses and ponies.     

Pharmacokinetics of tinidazole in the horse

Serum tinidazole concentrations were monitored in five clinically healthy adult horses after intravenous (i.v.) and oral administration of the drug (15 mg/kg and 25 mg/kg, respectively). After i.v. administration, the mean residence time was 7.0 h, the elimination half-life 5.2 h and the body clearance rate 1.6 ml/min/kg. The distribution volume was found to be 660 ml/kg. After oral administration, the mean residence time was 8.5 h, the absorption half-life 1.1 h and the bioavailability essentially 100%. In view of the in-vitro sensitivities of various anaerobic bacteria, a dosage of 10-15 mg/kg of tinidazole, orally, at 12-h intervals, can be recommended for the treatment of anaerobic infections in horses.     

The effects of xylazine,detomidine, acepromazine and butorphanol on equine solid phase gastric emptying rate

The aim of this study was to measure the effects of specific commonly used sedative protocols on equine solid phase gastric emptying rate, using the 13C-octanoic acid breath test (13C-OABT). The gastric emptying of a standard 13C-labelled test meal was measured once weekly in 8 mature horses over two 4 week treatment periods. Each horse acted as its own control. In treatment Period 1, saline (2 ml i.v.), xylazine (0.5 mg/kg i.v.), detomidine (0.01 mg/kg i.v.) or detomidine/butorphanol combination (0.01/0.02 mg/kg i.v.) was administered in randomised order after ingestion of the test meal. During treatment Period 2, test meal consumption was followed by saline, xylazine (1.0 mg/kg i.v.), or detomidine (0.03 mg/kg i.v.) administration, or preceded by acepromazine (0.05 mg/kg i.m.) in randomised order. The 13C:12C ratio of sequential expiratory breath samples was determined by isotope ratio mass spectrometry, and used to measure the gastric half-emptying time, t 1/2, and duration of the lag phase, t lag, for each of the 64 tests. In treatment Period 1, detomidine/butorphanol prolonged both t 1/2 and t lag with respect to xylazine 0.5 mg/kg and the saline control (P < 0.05). In Period 2, detomidine 0.03 mg/kg delayed each parameter with respect to saline, acepromazine and xylazine 1.0 mg/kg (P < 0.001). Xylazine 1.0 mg/kg also lengthened t lag relative to the saline control (P = 0.0004), but did not cause a significant change in t 1/2. Comparison of treatment periods showed that the inhibitory effect of detomidine on gastric emptying rate was dose related (P<0.05). These findings may have clinical significance for case selection when these agents are used for purposes of sedation and/or analgesia.     

Pharmacokinetics and metabolic effects of triamcinolone acetonide and their possible relationships to glucocorticoid-induced laminitis in horses

Experiments were performed to establish the pharmacokinetics of triamcinolone acetonide and the effects of the glucocorticoid on glucose metabolism in horses. The pharmacokinetics after intravenous (i.v.) dosing was best described by a three-compartment open model. There was rapid distribution from the central compartment followed by two phases of elimination. The half-life of the rapid elimination phase was 83.5 min and of the slower phase was 12 h. The term (Vss/Vc)-1was 12.3 indicating extensive distribution into the tissues. Triamcinolone acetonide given i.v. or intramuscularly (i.m. ) induced a prolonged period of hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia. Significant changes in plasma glucagon and serum non-esterified fatty acids were not observed. These observations suggest that the hyperglycaemia was a result of decreased glucose utilization by tissues and increased gluconeogenesis. The effects on glucose metabolism persisted for 3-4 days after triamcinolone was given i.m. at 0.05 mg/kg, the upper limit of the recommended dose range, and for 8 days when given at 0. 2 mg/kg. These observations, together with recent evidence implicating inhibition of glucose metabolism in the pathogenesis of equine laminitis, indicated that triamcinolone-induced laminitis may be associated with the long duration of action of the glucocorticoid when higher than recommended doses or when repeated doses are given.     

The pharmacokinetics of meclofenamic acid in the horse

The pharmacokinetics of meclofenamic acid were studied in Thoroughbred horses and in ponies. After intravenous (i.v.) administration of either 2 mg/kg or 4 mg/kg sodium meclofenamate the elimination half-life was of the order of 0.9 h while the volume of distribution was found to be 0.128 litre/kg. Elimination was in accordance with a one-compartment model. Following oral administration of either meclofenamic acid (4 mg/kg) or sodium meclofenamate (4 mg/kg) a much longer terminal half-life than that calculated for K _el from i.v. data was found. This anomaly indicated that the 'flip-flop' phenomenon was present, i.e. K _a exceeded K _el. More rapid and higher peak levels occurred following sodium meclofenamate than meclofenamic acid, although total bioavailability was similar. Studies in ponies with meclofenamic acid showed a lower absorption than that found in Thoroughbreds. Overnight fasting before meclofenamic acid administration did not alter the rate or extent of absorption. Intramuscular administration of sodium meclofenamate resulted in low plasma concentrations and after 25 h only 46% of the drug had been absorbed.     

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%.     

Interactions between chloramphenicol, acepromazine, phenylbutazone, rifampin and thiamylal in the horse

The potential for interactions between chloramphenicol, phenylbutazone, acepromazine and thiamylal and chloramphenicol, rifampin, and phenylbutazone were evaluated in two groups of experiments. In the first, five horses were given thiamylal intravenously (iv) (6.6 mg/kg) after pretreatment with acepromazine, and the time of recumbency was determined. Administration of chloramphenicol iv (25 mg/kg) 1 h prior to anaesthesia significantly lengthened the recumbency time from 21.8 +/- 4.8 mins to 36.0 +/- 8.3 mins. There was an apparent but not statistically significant decrease in recumbency time when phenylbutazone (4.4 mg/kg) was administered iv daily for 4 days prior to anaesthesia. In the second series of experiments, phenylbutazone (4.4 mg/kg), chloramphenicol (25 mg/kg) and rifampin (10 mg/kg) were administered in various sequences to five different horses. Chloramphenicol pretreatment produced a significant decrease in the elimination rate and rifampin a significant increase in the elimination rate of phenylbutazone. The half-life of elimination of phenylbutazone alone was about 4 h. Following four days pretreatment with rifampin it was approximately 2.7 h, it was approximately 5.6 h and 9.5 h, respectively, when chloramphenicol was administered in one dose 1 h before or two doses 12 h and 1 h before phenylbutazone.     

Repeated administration of trimethoprim/sulfadiazine in the horse--pharmacokinetics, plasma protein binding and influence on the intestinal microflora

Six healthy adult horses were given repeated administrations of trimethoprim/ sulfadiazine (TMP/SDZ) intravenously (i.v.) (2.5 mg/kg TMP and 12.5 mg/kg SDZ) and orally (p.o.) as a paste (5 mg/kg TMP and 25 mg/kg SDZ). Both formulations were given twice daily for 5 days, with a 3-week interval between i.v. and oral administration. The influence of the drug combination on the intestinal microflora was examined and the plasma concentrations, pharmacokinetic parameters and plasma protein binding were determined. There were no major changes in the bacterial intestinal flora and no clinical evidence of gastrointestinal disturbances following the i.v. and oral TMP/SDZ administration. An initial reduction in the number of coliform bacteria during the treatment was notable, though with no evident difference between i.v. and oral treatment. The minimum concentration during a dose interval at steady state (Cminss), the elimination half-life (t1/2beta) and the mean residence time (MRT) were significantly greater after oral administration compared to i.v. for both TMP and SDZ. The plasma protein binding was measured to be 20% for SDZ and 35% for TMP. Oral administration of TMP/SDZ in a dose of 30 mg/kg given twice daily in the form of paste appeared as a satisfactory method for obtaining plasma levels above MIC (minimum inhibitory concentration in vitro) values during the interdosing interval.     

Pharmacokinetics and pharmacodynamics of epsilon-aminocaproic acid in horses

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of epsilon-aminocaproic acid (EACA), including the effects of EACA on coagulation and fibrinolysis in healthy horses. ANIMALS: 6 adult horses. PROCEDURES: Each horse received 3.5 mg of EACA/kg/min for 20 minutes, i.v. Plasma EACA concentration was measured before (time 0), during, and after infusion. Coagulation variables and plasma alpha(2)-antiplasmin activity were evaluated at time 0 and 4 hours after infusion; viscoelastic properties of clot formation were assessed at time 0 and 0.5, 1, and 4 hours after infusion. Plasma concentration versus time data were evaluated by use of a pharmacokinetic analysis computer program. RESULTS: Drug disposition was best described by a 2-compartment model with a rapid distribution phase, an elimination half-life of 2.3 hours, and mean residence time of 2.5 +/- 0.5 hours. Peak plasma EACA concentration was 462.9 +/- 70.1 microg/mL; after the end of the infusion, EACA concentration remained greater than the proposed therapeutic concentration (130 microg/mL) for 1 hour. Compared with findings at 0 minutes, EACA administration resulted in no significant change in plasma alpha(2)-antiplasmin activity at 1 or 4 hours after infusion. Thirty minutes after infusion, platelet function was significantly different from that at time 0 and 1 and 4 hours after infusion. The continuous rate infusion that would maintain proposed therapeutic plasma concentrations of EACA was predicted (ie, 3.5 mg/kg/min for 15 minutes, then 0.25 mg/kg/min). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that EACA has potential clinical use in horses for which improved clot maintenance is desired.     

A pharmacokinetic study of phenobarbital in mature horses after oral dosing

The pharmacokinetics of phenobarbital were determined in six mature horses after a single oral dose. Horses were administered a 5.5 mg/kg of body weight oral dose of phenobarbital tablets. Based on the combined evaluation of i.v. and oral results, phenobarbital displayed two-compartment pharmacokinetics in the horse with a terminal half-life of 19.0 +/- 4.4 (mean +/- SD) h. This half-life is considerably shorter than those reported for dogs and humans. The steady-state volume of distribution (Vdss/F) and the total body clearance (Clt/F) of phenobarbital were 0.753 +/- 0.115 l/kg and 27.9 +/- 9.2 ml/h/kg, respectively. The average extent of oral absorption was 101% with a range of 76 to 124% among the six horses. Examination of the absorption kinetics demonstrated a biphasic absorption process in four horses with a rapid absorption followed by a slower absorption phase. The mean residence time (MRT) was 36.9 +/- 4.1 h and the mean residence time for oral absorption (MRTabs) was 11.3 h. Based on the results of the present study, an oral dosing regimen of 11 mg/kg of body weight every 24 h can be recommended.     

Fexofenadine in horses: pharmacokinetics, pharmacodynamics and effect of ivermectin pretreatment

The pharmacokinetics and the effects on inhibition of histamine-induced cutaneous wheal formation of the histamine H1-antagonist fexofenadine were studied in horse. The effect of ivermectin pretreatment on the pharmacokinetics of fexofenadine was also examined. After intravenous infusion of fexofenadine at 0.7 mg/kg bw the mean terminal half-life was 2.4 h (range: 2.0-2.7 h), the apparent volume of distribution 0.8 L/kg (0.5-0.9 L/kg), and the total body clearance 0.8 L/h/kg (0.6-1.2 L/h/kg). After oral administration of fexofenadine at 10 mg/kg bw bioavailability was 2.6% (1.9-2.9%). Ivermectin pretreatment (0.2 mg/kg, p.o.) 12 h before oral fexofenadine decreased the bioavailability to 1.5% (1.4-2.1%). In addition, the area under the plasma concentration-time curve decreased 27%. Ivermectin did not affect the pharmacokinetics of i.v. administered fexofenadine. Ivermectin may influence fexofenadine absorption by interfering in intestinal efflux and influx pumps, such as P-glycoprotein and the organic anion transport polypeptide family. Oral and i.v. fexofenadine significantly decreased histamine-induced wheal formation, with a maximal duration of 6 h. A pharmacokinetic/pharmacodynamic link model indicated that fexofenadine in horse has antihistaminic effects at low plasma concentrations (EC50 = 16 ng/mL). However, oral treatments of horses with fexofenadine may not be suitable due to the low bioavailability.