Phenylbutazone is an acidic, lipophilic, nonsteroidal anti-inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphenbutazone, y-hydroxyphenylbutazone and y-hydroxyoxyphenbutazone. account for some 25-30% of administered dose over 24 h. The plasma half-life of phenylbutazone and termination of its pharmacological action are determined primarily by its rate of hepatic metabolism. Phenylbutazone acts by inhibiting the cyclooxygenase enzyme system, which is responsible for synthesis of prostanoids such as PGE?. It appears to act on prostaglalidin-H synthase and prostacyclin synthase, after conversion by prostaglandin-H synthase to reactive intermediates. It markedly reduces prostanoid-dependent swelling, edema, erythema, and hypersensitivity to pain in inflamed tissues. Its principal use in the horse is for treatment of soft tissue inflammation. Phenylbutazone is highly bound (> 98%) to plasma protein. After i.v. injection, blood levels decline with an elimination half-life of 3-10 h. The plasma kinetics of phenylbutazone may be dose dependent, with the plasma half-life increasing as the drug dosage level increases. Plasma residues of the drug at 24 h after a single i.v. dose of 2 g/450 kg average about 0.9 pg/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approxiniately 4.5 pg/ml on Day 5 after 4 days of dosing. Approximately similar blood levels are found after a combination of oral and i.v. dosing. Experiments on large numbers of horses in training have been undertaken to ascertain the population distributions of residual blood levels after such dosing schedules. Absorption of phenylbutazone from the gastrointestinal tract is influenced by the dose administered and the relationship of dosing to feeding. Access to hay can delay the time of peak plasma concentration to 18 h or longer. Under optimal conditions, the bioavailability of oral phenylbutazone is probably in the region of 70%. Paste preparations may be more slowly absorbed than other preparations and yield higher residual plasma levels at 24 h after dosing, but further controlled studies are required. Phenylbutazone is easily detected in the plasma and urine of horses but concentrations in saliva are low. It is quantitated for forensic purposes by HPLC. The variability of this method between laboratories is about k 25%. Increasing urinary pH increases the urinary concentration of phenylbutazone and its metabolites up to 200-fold. However, urinary pH has little effect on the plasma half-life of phenylbutazone, which is determined mainly by hepatic metabolism and possibly by biliary secretion. Phenylbutazone has a narrow therapeutic index in the horse. If the administered dose is greater than recommended by the manufacturer, toxic effects may be produced, especially if high dose administration is maintained for more than a few days. Signs of toxicity include anorexia, depression, oral and GI ulcers, plasma protein losing enteropathy, and death from shock. Other side-effects include toxic neutropenia, hepatotoxicity and renal papillary necrosis; the latter may occur if access to water is restricted. If phenylbutazone is withdrawn in the early stages of toxicity, the prognosis is good. Late withdrawal is associated with delayed recovery. Death may occur up to 50 days after withdrawal of the drug. This toxicity can be antagonized by administration of prostaglandins.
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This work was supported by a grant entitled ‘Masking by phenylbutazone in equine drug testing: an analysis’ from the Kentucky Equine Drug Research Council and the Kentucky State Racing and Harness Racing Commission.
Tobin, Thomas; Chay, S.; Kamerling, S.; Woods, W. E.; Weckman, T. J.; Blake, J. W.; and Lees, P., "Phenylbutazone in the horse: a review" (1986). Maxwell H. Gluck Equine Research Center Faculty Publications. 94.