Principles of drug disposition in the horse

This article is intended to give the reader an understanding of the mathematic and conceptual framework underlying equine pharmacology. The methods by which the veterinary practitioner determines drug concentrations, disposition, and bioavailability are discussed.     

The disposition and excretion of ethanol by the horse

The disposition and excretion of ethanol in horses has been studied after oral administration. Ethanol was rapidly absorbed from the gastrointestinal tract. The highest concentration of ethanol in blood and in parotid saliva occurred within 1 h of administration. The concentrations were dose dependent. The mean rate of disappearance of ethanol from blood was 6.3 mg/100 ml/h. The ratio of the concentration of ethanol in parotid saliva to that in venous blood was 1.16:1. The mean rate of elimination was 51 mg/kg body weight/h. The proportion of ethanol excreted in the urine was 0.7% of the dose.     

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.     

The effect of phenylbutazone on the plasma disposition of penicillin G in the horse

A pilot study in two ponies showed that the plasma concentrations of intramuscularly administered procaine penicillin were higher if phenylbutazone was administered concurrently. In two other trials, each involving five horses, intravenous sodium penicillin was administered with and without concurrent intravenously injected phenylbutazone, and procaine penicillin was injected intramuscularly with and without oral phenylbutazone. In both cases the plasma concentrations of penicillin were higher when phenylbutazone was given. The pharmacokinetic parameters indicated that the effect was probably due to a lower peripheral distribution because the penetration of penicillin into the tissues was greatly reduced.     

Rifampin disposition in the horse: effects of age and method of oral administration

The effects of time and method of administration of rifampin with respect to feeding were evaluated in five mature horses. There was a significant (P less than or equal to 0.05) delay in time of maximum serum concentration and an apparent but not significant decrease in oral absorption when rifampin was given as a top dressing on grain as compared with administration in corn syrup 2 h before or 2 h after feeding. Although there were no differences between administration before or after feeding, administration 2 h prior to feeding was selected as the method of choice for future experiments. The effects of age on rifampin disposition were subsequently examined using this method of administration in six, 1-week old foals. Rifampin (10 mg/kg) was given at increasing age from 1 through 10 weeks and the pharmacokinetic disposition parameters compared. There were significant differences in the slope of the elimination phase (beta) and area under the curve (AUC) at 1 week through 6 weeks compared with 10 weeks or with values in the five mature horses.     

Pharmacokinetic disposition of an immediate-release aminophylline and a sustained-release theophylline formulation in the horse

The pharmacokinetic disposition of theophylline was determined by high-performance liquid chromatographic analysis of plasma samples from six healthy, adult horses following the administration of intravenous aminophylline (dosed at 9.94 mg/kg as theophylline), immediate-release aminophylline tablets (dosed at 9.94 mg/kg as theophylline), and sustained-release theophylline tablets (dosed at 20 mg/kg). The elimination rate constant (lambda z), apparent volume of distribution (Vz), and clearance (Cl) determined by compartmental analysis of the intravenous data were 0.07 +/- 0.01 h-1, 0.80 +/- 0.06 l/kg, and 0.06 +/- 0.01 l/kg/h (mean +/- SD), respectively. Mean residence time determined by statistical moment theory of the oral data was different (P less than 0.05) for the immediate-release aminophylline (13.8 +/- 2.8 h) and sustained-release theophylline (18.2 +/- 2.3 h) formulation. Immediate-release aminophylline tablets quickly achieved peak theophylline plasma concentration of 11.51 +/- 1.4 micrograms/ml at 1.6 +/- 0.6 h while the sustained-release theophylline tablets were more slowly absorbed and achieved peak theophylline concentrations of 17.20 +/- 1.3 micrograms/ml at 7.3 +/- 1.0 h. Absolute bioavailability was 87% for the immediate-release and 97% for the sustained-release formulation. Using the principle of superposition, a loading dose of 20 mg/kg of the sustained-release formulation followed by maintenance doses of 15 mg/kg every 24 h was predicted to achieve trough-peak theophylline plasma concentrations between 6 and 17 micrograms/ml.     

Disposition and tolerance of suxibuzone in horses.

Suxibuzone (SBZ), a nonsteroidal anti-inflammatory drug, was administered to 6 horses at a dose rate of 7.5 mg/kg bwt by intravenous (i.v.) route. Plasma and synovial fluid concentrations of suxibuzone and its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ), were measured simultaneously by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Plasma SBZ concentrations rapidly decreased and were not detectable beyond 20 min after treatment. The parent drug was not detected in any synovial fluid samples. Average maximum plasma concentrations of PBZ (16.43 microg/ml) and OPBZ (2.37 microg/ml) were attained at 0.76 and 7.17 h, respectively. The mean residence time (MRT) of PBZ was 6.96 h in plasma. Oxyphenbutazone plasma concentrations were below those reached by phenylbutazone during the first 12 h after suxibuzone administration, even though its values were detectable for at least 24 h (MRT = 10.65 h). Plasma concentrations of PBZ and OPBZ exceeding EC50 and IC50 of TXB2 and PGE2 were reached by at least 12 h. Synovial fluid concentrations of PBZ and OPBZ were 2.87+/-0.37 microg/ml and 0.97+/-0.08 microg/ml at 9 h after suxibuzone administration and exceeded IC50 of PGE2 for at least this time. In the present study, suxibuzone was well tolerated following i.v. injection.     

The use of phenylbutazone in the horse

This review presents a brief historical prospective of the genesis of regulated medication in the US racing industry of which the nonsteroidal anti-inflammatory drug (NSAID) phenylbutazone (PBZ) is the focus. It presents some historical guideposts in the development of the current rules on the use of PBZ by racing jurisdictions in the US. Based on its prevalent use, PBZ remains a focus of attention. The review examines the information presented in a number of different models used to determine the effects and duration of PBZ in the horse. They include naturally occurring lameness and reversible-induced lameness models that directly examine the effects and duration of the administration of various doses of PBZ. The review also examines indirect plasma and tissue models studying the suppression of the release of arachidonic acid-derived mediators of inflammation. The majority of studies suggest an effect of PBZ at 24 h at 4.4 mg/kg. This reflects and substantiates the opinion of many clinical veterinarians, many of whom will not perform a prepurchase lameness examination unless the horse is free of NSAID. This remains the opinion of many regulatory veterinarians responsible for the prerace examination of race horses that they wish to examine a horse without the possibility of an NSAID interfering with the examination and masking possible musculoskeletal conditions. Based on scientific studies, residual effects of PBZ remain at 24 h. The impact of sustained effect on the health and welfare of the horse and its contribution to injuries during competition remains problematic.     

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.     

The disposition of albendazole in sheep

Albendazole (ABZ) was administered intraruminally at 4.75 mg/kg to sheep fitted with a permanent bile-duct cannula to determine if its metabolites might contribute to its flukicidal action. ABZ metabolism was consistent with first-pass clearance by the liver, resulting in ABZ sulphoxide (ABZ-SO) and ABZ sulphone (ABZ-SO2) being present in plasma at maximum concentrations (mean Cmax +/- SD) of 2.0 +/- 0.2 micrograms/ml and 0.4 +/- 0.1 micrograms/ml after 8 +/- 3 h and 24 +/- 5 h, respectively. ABZ-SO, but more particularly ABZ-SO2, appeared to bind to plasma proteins but their clearance rates from plasma were similar. Biliary ABZ metabolites were mainly unconjugated ABZ-SO and 2OH-ABZ-SO (8.0% dose) or conjugated glucuronide and sulphate esters (6.3% dose) mainly of 2OH-ABZ-SO and 2OH-ABZ-SO2. The concentration of the major biliary metabolite, unconjugated ABZ-SO, followed a similar time profile to that of ABZ-SO in plasma except that Cmax was much higher (6.2 +/- 2.2 micrograms/ml). Intraruminal administration of ABZ reduced bile flow rate by 30% which may be attributable to an inhibitory effect of ABZ on microtubule formation in hepatic secretory cells. It is suggested that ABZ is sequestered in the liver. This is unlikely to contribute to its flukicidal action, which is probably attributable to ingestion of ABZ-SO from bile and blood by the fluke.     

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.