The disposition of phenylbutazone (4.4 mg/kg), administered intravenously to six Welsh Mountain ponies, was described by a two-compartment open model. Pharmacokinetic parameters were not significantly different after morning dosing in comparison with afternoon dosing. When phenylbutazone (4.4 mg/kg) was administered orally to the same ponies, marked variations in time to peak concentrations were produced with different feeding schedules. When access to hay was permitted before and after dosing, the mean time to peak concentration was 13.2 +/- 1.2 h and double peaks in the plasma concentration-time curve were common. Double peaks were also encountered when phenylbutazone was given to ponies deprived of food prior to, and allowed access to hay after, dosing. In this circumstance, mean times to peak concentration were much shorter (3.8 +/- 1.3 h after morning dosing and 5.3 +/- 1.5 h followed afternoon dosing). Absorption was more regular and double peaks were less apparent when food was withheld both before and after dosing. In order to explain these findings, it is tentatively postulated that, whereas some of the administered dose of phenylbutazone may be absorbed quickly, some may become adsorbed on to the feed and subsequently released by fermentative digestion in the large intestine and/or caecum. The consequences of delayed absorption in fed animals for toxicity and clinical efficacy, and for the use of phenylbutazone in equestrian sports, are considered. Delayed absorption in ponies given access to hay was not accompanied by a significant reduction in total absorption. Bioavailability was estimated to be approximately 69% in fed and 78% in unfed ponies. Estimates of bioavailability gave similar values for morning (72%) and afternoon (71%) dosing.
The clinically recommended dose rate of phenylbutazone (4.4 mg/kg) was administered intravenously as a single dose to five Welsh Mountain ponies. Distribution of phenylbutazone and its active metabolite oxyphenbutazone into body fluids was studied by measuring concentrations in plasma, tissue-cage fluid, peritoneal fluid and acute inflammatory exudate harvested from a polyester sponge model of inflammation. The ready penetration of phenylbutazone into inflammatory exudate was demonstrated by the relatively high mean value for Cmax of 12.4 micrograms/ml occurring at a time of 4.6 h and a mean AUC0-24 of 128 microgram X h/ml. A high mean exudate:plasma AUC0-24 ratio of 0.83 was recorded. Plasma:exudate concentration ratios for phenylbutazone were initially greater than and subsequently less than one; the slower clearance from exudate was indicated by approximate t1/2 beta) values of 4.8 and 24 h for plasma and exudate, respectively. These findings may help to explain the relatively long duration of action of phenylbutazone, in spite of a plasma elimination half-life of less than 5 h. Lower values of Cmax and AUC0-24 for phenylbutazone passage into peritoneal fluid (6.3 micrograms/ml and 45 micrograms X h/ml) were recorded, and a limited number of sampling times indicated a similar degree of penetration as into tissue cage fluid. Mean concentrations of oxyphenbutazone in all fluids were lower than phenylbutazone concentrations at all times, but ready penetration of the metabolite into body fluids, especially into inflammatory exudate, occurred suggesting that oxyphenbutazone may contribute to the anti-inflammatory effect. The hyperaemia of acute inflammation and the high protein levels in inflammatory exudate may both assist passage of phenylbutazone and oxyphenbutazone into exudate.
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...
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