Pharmacokinetics and disposition of clenbuterol in the horse.

The pharmacokinetics of clenbuterol (CLB) following a single intravenous (i.v.) and oral (p.o.) administration twice daily for 7 days were investigated in thoroughbred horses. The plasma concentrations of CLB following i.v. administration declined mono-exponentially with a median elimination half-life (t(1/2k)) of 9.2 h, area under the time-concentration curve (AUC) of 12.4 ng.h/mL, and a zero-time concentration of 1.04 ng/mL. Volume of distribution (V(d)) was 1616.0 mL/kg and plasma clearance (Cl) was 120.0 mL/h/kg. The terminal portion of the plasma curve following multiple p.o. administrations also declined mono-exponentially with a median elimination half-life (t(1/2k)) of 12.9 h, a Cl of 94.0 mL/h/kg and V(d) of 1574.7 mL/kg. Following the last p.o. administration the baseline plasma concentration was 537.5 +/- 268.4 and increased to 1302.6 +/- 925.0 pg/mL at 0.25 h, and declined to 18.9 +/- 7.4 pg/mL at 96 h. CLB was still quantifiable in urine at 288 h following the last administration (210.0 +/- 110 pg/mL). The difference between plasma and urinary concentrations of CLB was 100-fold irrespective of the route of administration. This 100-fold urine/plasma difference should be considered when the presence of CLB in urine is reported by equine forensic laboratories.

Tissue distribution of clenbuterol in the horse.

Plasma and tissue concentrations of clenbuterol (CLB) were determined following oral (p.o.) administration of 1.6 microg/kg twice daily (b.i.d.) for 2 weeks. Horses were administered the last dose on morning of day 15, killed at 0.25, 24, 48, and 72 h post-administration. At 0.25 h, the highest tissue concentrations of CLB were found in the liver (16.21 ng/g), lung (6.48 ng/g), left ventricle (4.99 ng/g), kidney (3.35 ng/g), bronchi (2.56 ng/g), right ventricle (2.08 ng/g), and eye fluids (1.09 ng/g) all of which were higher than that of plasma (1.10 ng/mL). The elimination half-lives (t(1/2k)) for CLB in tissues ranged from 21.2 to 56.3 h, the longest were in the eye fluids (56.9 h), spleen (21.2 h), cerebrum (27.1 h), cerebellum (21.5) and cecum (23.7 h). The t(1/2k) for plasma was 10.9 h. Tissue/plasma ratios of liver (14.7), lung (5.9), left ventricle (4.6), kidney (3.1), bronchi, (2.3) and right ventricle (1.9) were high at 0.25 h and remained elevated up to 72 h. Accumulation and sustained high concentration of CLB relative to plasma in these tissues contributed to the prolonged elimination and the ability to quantify CLB in plasma and urine for a prolonged period.

EIPH: postrace endoscopic evaluation of Standardbreds and Thoroughbreds.

The incidence and severity of exercise-induced pulmonary haemorrhage (EIPH) in the 2 most commonly raced horse breeds, Thoroughbreds (TB) and Standardbreds (STD), were studied, with particular interest in the possible influence of frusemide (F) and/or the breed (or running gait) on EIPH. The appearance of blood within the trachea was semi-quantified using a published 5-point system, with zero assigned when no blood was observed, and numbers 1-4 assigned with increasing amounts of blood. Considering each endoscopic examination as a separate event, approximately 75% of the postrace endoscopic examinations had blood-scores of 1, 2, 3, or 4, regardless of breed or F administration. For horses examined twice, the chances of finding blood-scores of 1 or greater in either of the examinations increased to approximately 95%. All horses examined 3 or more times had endoscopic blood-scores of 1 or greater following one or more races, again, irrespective of the breed or F administration. Mean +/- s.e. 'blood scores' were 1.5 +/- 0.1 and 1.8 +/- 0.2 for TB, and 1.4 +/- 0.2 and 1.2 +/- 0.1 for STD racing with and without prerace F, respectively. Therefore, there was no apparent effect of breed (or possibly racing gait) on EIPH, and no differences in the incidence or severity of EIPH were observed between horses with or without prerace frusemide administration.

Disposition, elimination, and bioavailability of phenytoin and its major metabolite in horses.

OBJECTIVE: To determine pharmacokinetics and excretion of phenytoin in horses. ANIMALS: 6 adult horses. PROCEDURE: Using a crossover design, phenytoin was administered (8.8 mg/kg of body weight, IV and PO) to 6 horses to determine bioavailability (F). Phenytoin also was administered orally twice daily for 5 days to those same 6 horses to determine steady-state concentrations and excretion patterns. Blood and urine samples were collected for analysis. RESULTS: Mean (+/- SD) elimination half-life following a single IV or PO administration was 12.6+/-2.8 and 13.9+/-6.3 hours, respectively, and was 11.2+/-4.0 hours following twice-daily administration for 5 days. Values for F ranged from 14.5 to 84.7%. Mean peak plasma concentration (Cmax) following single oral administration was 1.8+/-0.68 microg/ml. Steady-state plasma concentrations following twice-daily administration for 5 days was 4.0+/-1.8 microg/ml. Of the 12.0+/-5.4% of the drug excreted during the 36-hour collection period, 0.78+/-0.39% was the parent drug phenytoin, and 11.2+/-5.3% was 5-(phydroxyphenyl)-5-phenylhydantoin (p-HPPH). Following twice-daily administration for 5 days, phenytoin was quantified in plasma and urine for up to 72 and 96 hours, respectively, and p-HPPH was quantified in urine for up to 144 hours after administration. This excretion pattern was not consistent in all horses. CONCLUSIONS AND CLINICAL RELEVANCE: Variability in F, terminal elimination-phase half-life, and Cmax following single or multiple oral administration of phenytoin was considerable. This variability makes it difficult to predict plasma concentrations in horses after phenytoin administration.

Quantification of phenytoin and its metabolites in equine plasma and urine using high-performance liquid chromatography.

A reliable and sensitive method for the extraction and quantification of phenytoin (5,5'-diphenylhydantoin), its major metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and minor metabolite, 5-(m-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) in horse urine and plasma is described. The method involves the use of solid-phase extraction (SPE), liquid-liquid extraction (LLE), enzyme hydrolysis (EH) and high-performance liquid chromatography (HPLC). The minor metabolite, 5-(m-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) was not present in a reliably quantifiable concentration in all samples. The new method described was successfully applied in the pharmacokinetic studies and elimination profile of phenytoin and p-HPPH following oral or intravenous administration in the horse.

The effects of frusemide on racing times of Standardbred pacers.

Seven hundred and eighty-eight Standardbred pacers competing in 8378 races at one racetrack were analysed to determine the effects of the administration of prerace frusemide on racing times (RT). Frusemide was administered i.v. 4 h before the race to pacers diagnosed with exercise-induced pulmonary haemorrhage (EIPH). Of the pacers, starting in the 1997 racing season, 32.5% received prerace frusemide. This study demonstrated that administration of frusemide prior to racing significantly decreased RT. There was an overall significant decrease (P<0.00001) in RT of 0.67 s. The overall RT for horses, geldings, and females, were mean +/- s.e 117.91 +/- 0.06, 118.20 +/- 0.03 and 118.86 +/- 0.04, respectively. RT progressively decreased until age 6 and increased thereafter. Horses, geldings and females ran a mean of 0.46, 0.31 and 0.74 s faster, respectively, with prerace administration of frusemide. This decrease in RT following prerace administration was most pronounced in younger pacers. In this study, a greater percentage of older pacers received prerace frusemide; however, the effect of frusemide on RT was decreasing with age. Prerace venous acid-base screening was performed in 2729 of the pacers competing. Pennsylvania Harness Racing Commission Regulations disqualify Standardbreds from racing with a base excess of over 10 and 12 mmol/l for Standardbreds without and with prerace administration of frusemide. The prerace venous acid-base levels were not significantly related to RT and, for those Standardbreds also sampled following the race, there was no correlation between pre- and postrace acid-base status.

Pharmacokinetics of penicillin G procaine versus penicillin G potassium and procaine hydrochloride in horses.

OBJECTIVE: To compare the pharmacokinetics of penicillin G and procaine in racehorses following i.m. administration of penicillin G procaine (PGP) with pharmacokinetics following i.m. administration of penicillin G potassium and procaine hydrochloride (PH). ANIMALS: 6 healthy adult mares. PROCEDURE: Horses were treated with PGP (22,000 units of penicillin G/kg of body weight, i.m.) and with penicillin G potassium (22,000 U/kg, i.m.) and PH (1.55 mg/kg, i.m.). A minimum of 3 weeks was allowed to elapse between drug treatments. Plasma and urine penicillin G and procaine concentrations were measured by use of high-pressure liquid chromatography. RESULTS: Median elimination phase half-lives of penicillin G were 24.7 and 12.9 hours, respectively, after administration of PGP and penicillin G potassium. Plasma penicillin G concentration 24 hours after administration of penicillin G potassium and PH was not significantly different from concentration 24 hours after administration of PGP. Median elimination phase half-life of procaine following administration of PGP (15.6 hours) was significantly longer than value obtained after administration of penicillin G potassium and PH (1 hour). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that i.m. administration of penicillin G potassium will result in plasma penicillin G concentrations for 24 hours after drug administration comparable to those obtained with administration of PGP Clearance of procaine from plasma following administration of penicillin G potassium and PH was rapid, compared with clearance following administration of PGP.

Quantification of penicillin-G and procaine in equine urine and plasma using high-performance liquid chromatography.

A rapid and sensitive method for the extraction and quantification of penicillin-G and procaine in horse urine and plasma samples has been successfully developed. The method involves the use of solid-phase extraction (SPE) for penicillin-G, liquid-liquid extraction (LLE) for procaine, and high-performance liquid chromatography (HPLC) for the quantification of penicillin-G and procaine. The new method described here has been successfully applied in the pharmacokinetic studies of procaine, penicillin-G and procaine-penicillin-G administrations in the horse.

Effect of high-intensity exercise on arterial blood gas tensions and upper airway and cardiac function in clinically normal quarter horses and horses heterozygous and homozygous for hyperkalemic periodic paralysis.

OBJECTIVE: To determine the effect of exercise on arterial blood gas tensions and upper airway and cardiac function in clinically normal Quarter Horses and horses heterozygous and homozygous for hyperkalemic periodic paralysis (HYPP). ANIMALS AND PROCEDURE: 5 clinically normal Quarter Horses, and 5 heterozygous and 2 homozygous HYPP-affected horses were examined before, during, and after exercise on a high-speed treadmill. Arterial blood gas tensions, ECG, and echocardiogram were obtained prior to exercise. Upper airway endoscopy, collection of arterial blood samples, and continuous electrocardiography were performed during a high-intensity stepwise exercise test. An ECG was obtained within 1-minute after completion of the final step. RESULTS: None of the horses homozygous or heterozygous for HYPP had signs of weakness or muscle fasciculations before, during, or after exercise. Horses homozygous for HYPP had intermittent laryngospasm, dynamic pharyngeal collapse, and appreciable hypoxemia, hypercapnia, and ventricular premature contractions during exercise. Heterozygous and clinically normal horses did not have any abnormalities. Potassium concentration increased significantly above the baseline reference range during exercise in all groups of horses. CONCLUSIONS: Horses homozygous for HYPP had laryngospasm and dynamic pharyngeal collapse associated with exercise, most likely secondary to increase in potassium concentration. Upper airway dysfunction is the most likely cause of hypoxemia and hypercapnia. Cardiac arrhythmias were most likely caused by a combination of hypoxemia and hyperkalemia.