The effect of inflammation on the disposition of phenylbutazone in Thoroughbred horses

Abstract

The effect of inflammation on the disposition of phenylbutazone (PBZ) was investigated in Thoroughbred horses. An initial study (n = 5) in which PBZ (8.8 mg/kg) was injected intravenously twice, 5 weeks apart, suggested that the administration of PBZ would not affect the plasma kinetics of a subsequent dose. Two other groups of horses were given PBZ at either 8.8 mg/kg (n = 5) or 4.4 mg/kg (n = 4). Soft tissue inflammation was then induced by the injection of Freud's adjuvant and the administration of PBZ was repeated at a dose level equivalent to, but five weeks later than, the initial dose. Inflammation did not appear to affect the plasma kinetics or the urinary excretion of PBZ and its metabolites, oxyphenbutazone (OPBZ) or hydroxyphenylbutazone (OHPBZ) when PBZ was administered at 8.8 mg/kg. However, small but significant increases (P < 0.05) in total body clearance (CLB; 29.2 +/- 3.9 vs. 43.8 +/- 8.1 mL/ h.kg) and the volume of distribution, calculated by area (Vd(area); 0.18+/- 0.05 vs. 0.25 +/- 0.03 L/kg) or at steady-state (Vd(SS); 0.17 +/- 0.04 vs. 0.25 +/- 0.03 L/ kg), were obtained in horses after adjuvant injection, compared to controls, when PBZ was administered at 4.4 mg/kg which corresponded to relatively higher tissues concentrations and lower plasma concentrations (calculated) at the time of maximum peripheral PBZ concentration. Soft tissue inflammation also induced a significantly (P < 0.05) higher amount of OPBZ in the urine 18 h after PBZ administration but the total urinary excretion of analytes over 48 h was unchanged. These results have possible implications regarding the administration of PBZ to the horse close to race-day.

Pharmacokinetic/pharmacodynamic approach to assess irrelevant plasma or urine drug concentrations in postcompetition samples for drug control in the horse

“…Step 2 -computation of EPC: PBZ plasma clearance has been measured by many authors; mean reported values range from 16.3 to 41.3 ml/kg/h (Soma et al 1983;Lees et al 1987;Mills et al 1996). The most conservative value is obtained by taking the highest clearance value, i.e.…”

“…The most conservative value is obtained by taking the highest clearance value, i.e. 41.3 ml/kg/h (Mills et al 1996) or 991 ml/kg/24 h. Using equation 7: EPC = 4400 µg/kg/24 h = 4.44 µg/ml (7) 991 ml/kg/24 h This EPC is consistent with the EC 5 0 , which was directly determined by Toutain et al (1994) using a PK/PD approach in horses subjected to experimental arthritis (EC 5 0 from 1.5 to 4.3 µg/ml depending on the pharmacodynamic endpoint). Lees e t al.…”

The use of phenylbutazone in the horse

“…The production of muscle inflammation by the injection of Freud’s adjuvant did not affect the plasma kinetics and when administered 5 weeks apart there was no within horse variability indicating that the administration of PBZ did not affect the plasma kinetics of subsequent doses (Mills et al. , 1996).…”

“…The production of muscle inflammation by the injection of Freud's adjuvant did not affect the plasma kinetics and when administered 5 weeks apart there was no within horse variability indicating that the administration of PBZ did not affect the plasma kinetics of subsequent doses (Mills et al, 1996). This was verified by clinical observations that the plasma concentrations in a large population of horses were consistent postrace when a routine administration schedule was established in a horse and previous administrations did not affect subsequent doses.…”

Efeito da associação de furosemida e fenilbutazona sobre variáveis hidroeletrolíticas de cavalos antes e após a corrida

“…A fenilbutazona é usada por sua atividade antiinflamatória, analgésica e antipirética no tratamento de várias formas de claudicação (Booth e McDonald, 1992). É administrada com doses entre 2,2 e 8,8mg/kg, porém a dose de 4,4mg/kg é a mais utilizada em equinos (Mills et al, 1996). Esse anti-inflamatório inibe a atividade da cicloxigenase e a subsequente atividade de conversão de ácido araquidônico em metabólitos de prostaglandina (Hinchcliff, 1995).…”