Pharmacokinetics of phenylbutazone and its metabolites in the horse

Abstract

Summary Phenylbutazone was given orally to 2 groups of horses and the plasma levels of the drug and its 2 principal metabolites oxyphenbutazone and γ‐hydroxyphenylbutazone measured by high performance liquid chromatography. Animals in Group 1 received single oral doses in a range from 1.1 to 13.2 mg/kg and were sampled over the succeeding 24 h. Considerable individual variation was observed both in timing and magnitude of the plasma drug responses between horses, but 24 h after dosing a dear dose response relation was recorded. Group 2 horses were given the recommended therapeutic dosage regimen and sampled over 24 h periods twice weekly. After 4 days at 8.8 mg/kg in 2 divided doses mean peak plasma levels of phenylbutazone reached 24 μg/ml and showed evidence of cumulation. After 4 days at 4.4 mg/kg, peak plasma concentrations had fallen to 10 γg/ml and mean peak levels just failed to reach 4 γg/ml 3 days after reducing dosage to 2.2 mg/kg once daily. Plasma concentrations of oxyphenbutazone did not exceed 25 per cent of the parent drug and the y‐hydroxy metabolite was only just detectable and never exceeded 1 μg/ml. Résumé Du phénylbutazone a été administré oralement à deux groupes de chevaux, puis la concentration de la drogue et de ses deux principaux métabolites, I'oxyphenbutazone et l'hydroxyphénylbutazone, dans le plasma, a été mesurée à l'aide d'un chromatographe en phase liquide à hautes performances. Les animaux du groupe 1 ont reçu des doses orales uniques allant de 1, 1 à 13, 2 mg/kg, les échantillons étant prélevés au cours des 24 heures suivantes. On a pu observer des variations individuelles considérables au point de vue du moment d'apparition et de. l'amplitude des concentrations plasmiques entre les animaux, mais 24 heures après le dosage, une relation nette entre dose et réponse apparaît. Les bêtes du groupe 2 ont reçu la posologie thérapeutique recommandée et des prélèvements ont été effectués deux fois par semaine sur des périodes de 24 heures. Après quatre jours de traitement à 8, 8 mg/kg en deux doses séparées, les concentrations plasmiques de pointe moyennes de phénylbutazone atteignaient 24 μg/ml et on notait des signes d'effet cumulatif. Après quatre jours à 4 μg/kg, les concentrations plasmiques de pointe avaient baisséà 10 μg/ml; trois jours après avoir réduit le dosage à 2, 2 mg/kg pris une fois par jour, ces mêmes concentrations étaient juste en‐dessous de 4 μg/ml. Les concentrations plasmiques d'oxyphenbutazone ne dépassèrent pas 25% de celles de la drogue‐mère, tandis que l'hydroxymétabolite γétait juste détectable et ne dépassa jamais 1 μg/ml. Zusammenfassung Phenylbutazon wurde oral 2 Gruppen von Pferden verabreicht. Anschließend wurden die Plasmawerte der Droge und ihrer beiden wichtigsten Stoffwechselprodukte, Oxyphenbutazon und Hydroxyphenylbutazon, mit Hilfe eines Hochleistungs‐Chromatographen gemessen. Die Pferde der Gruppe 1 erhielten jeweils eine einzelne Dosis von 1, 1 bis 13, 2 mg/kg mit anschließender Probenentnahme während eines Zeitraums von 24 Stunden. Der zeitliche V...

Biochemical and haematological effects of phenylbutazone in horses

“…Because the main factor controlling the half-life of phenylbutazone in the horse is probably biotransformation in the liver (Gerring, Lees and Taylor 1981), impairment of hepatic function by phenylbutazone could be self-reinforcing and cause cumulation to toxic levels. The therapeutic and toxic effects of the drug are believed to be caused by cyclooxygenase inhibition and hence interference with the formation of cyclic endoperoxides, prostacylin, prostaglandins and thromboxanes (Higgs and Whittle 1980).…”

“…Phenylbutazone concentration was determined as previously described by Taylor, Lees and Gerring (1981). Low temperature centrifugation was carried out to minimise electrolyte shifts across the erythrocyte membrane.…”

Clinical pharmacology and therapeutic uses of non‐steroidal anti‐inflammatory drugs in the horse

“…It will be noted that phenylbutazone has improved its position in the equine potency listing. This is probably because the therapeutic activity of phenylbutazone in the horse is attained with plasma levels of 5 to 15 pg/ml (Jenny, Steinijans and Seifert 1979;Gerring, Lees and Taylor 1981) whereas, in man, plasma concentrations of 50 to 150 pg/ml appear to be required (Kampmann and Frey 1966). These differences may be attributable to a reportedly higher degree of protein binding in man (98.8 per cent) than in the horse (96 per cent) (Snow 1981).…”

Analysis of phenylbutazone residues in horse tissues with and without enzyme‐hydrolysis by LC‐MS/MS

“…It was well known that PBZ binds strongly to tissue proteins. [5][6][7][8] This paper describes the results of a comparative study that was conducted in our laboratory for the analysis of PBZ and OXPBZ with and without hydrolysis. This is the first reported study of the effect of β-glucoronidase hydrolysis on PBZ residues in incurred equine muscle, kidney, and liver tissues.…”