Phenylbutazone and oxyphenbutazone distribution into tissue fluids in the horse

Abstract

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.

Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma, exudate and transudate in sheep

“…Also following administration of PBZ (4.4 mg/kg, i.v.) to horses, a C max of 12.4 and 6.3 μg/mL in exudate and transudate, respectively was observed (Lees et al ., 1986). The high extravascular penetration of the drugs in sheep suggests a lower plasma protein drug binding in this species as the unbound drug in plasma is available to penetrate into both inflamed and non‐inflamed tissue‐cage fluids while the protein‐bound drug can only easily penetrate into the fluids at inflamed sites where inflammatory reaction results in vasodilatation and high capillary permeability.…”

“…It was unexpected that the elimination rate from transudate was slower (FM) than ( P < 0.05) or similar (PBZ) to ( P > 0.05) the elimiation from exudate and that no significant differences ( P > 0.05) in AUC ratios between exudate to plasma and transudate to plasma were observed in the present study. In common with most NSAIDs, FM and PBZ have been demonstrated to have slow exudate drug elimination rates and high AUC ratios of exudate to plasma compared with transudate in some animal species, at least in horses (Lees et al ., 1986, 1987), donkeys (Chenge et al ., 1996) and calves (Landoni et al ., 1995). This suggests a species difference between horses, donkeys and calves on one hand and sheep on the other hand.…”

A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation

“…These volumes of distribution are not high but, given that 2‐arylpropionates are highly bound to plasma protein, they represent good tissue penetration (Landoni & Lees, 1995, 1996a). In comparison, other NSAIDs which are also highly bound to plasma protein, such as flunixin and phenylbutazone, have somewhat lower (less than 0.2 L/kg) volumes of distribution in the horse (Higgins et al ., 1986; Lees et al ., 1986, 1987a, b).…”

Pharmacokinetics and in vitro efficacy of salicylic acid after oral administration of acetylsalicylic acid in horses

“…Extrapolated from synovial fluid concentrations measured in vitro , a COX-1 inhibitory effect can be expected in the joint for about 6 to 8 h (COX-1) and 2 h (COX-2). The results of the in vitro and in vivo studies [26] indicate that even if SA values in plasma and urine fall below the thresholds, one cannot exclude any therapeutic effect, especially since NSAIDs are generally known to accumulate in inflammatory exudate [27]. …”