Suxibuzone

The disposition of suxibuzone in the horse

A high performance liquid chromatographic method is described to determine the anti-inflammatory drug suxibuzone (SXB) and its major metabolites phenylbutazone (PBZ) and oxyphenbutazone (OPBZ) in equine plasma and urine. When suxibuzone (6 mg/kg) was administered intravenously (i.v.) or orally (p.o.) no parent drug was detected in plasma or in urine. The disposition of the metabolite PBZ (i.v.) could be described by a 2 compartment model with a beta half-life varying from 7.40 to 8.35 h. Due to severe side effects the use of i.v. suxibuzone should not be encouraged in the horse. PBZ and OPBZ were detected in plasma and urine after p.o. SXB administration. Peak plasma PBZ concentrations (8.8 +/- 3.0 micrograms/ml) occurred 6 h after oral dosing and the terminal exponential constant was 0.11 +/- 0.01 h-1. Phenylbutazone and oxyphenbutazone were detectable in urine (> 1 microgram/ml) for at least 36 h, after p.o. administration. SXB was not hydrolyzed in vitro by horse plasma. Equine liver homogenates however appeared to have a very high capacity for hydrolysing SXB, indicating that first-pass effect could be responsible for the rapid disappearance of this NSAID in the horse.

Comparison of the absorption, excretion, and metabolism of suxibuzone and phenylbutazone in humans

The absorption, excretion, and metabolism of a single oral dose of suxibuzone, a new nonsteroidal anti-inflammatory agent, in healthy male volunteers were compared with those of phenylbutazone. After oral administration of either suxibuzone or phenylbutazone, phenylbutazone, oxyphenbutazone, and gamma-hydroxyphenylbutazone were found in the plasma; phenylbutazone was the main metabolite of suxibuzone and phenylbutazone. In the urine, p-gamma-dihydroxyphenylbutazone and several glucuronide conjugates also were found. Spectrometric and/or enzymatic analysis showed that these glucuronide conjugates were suxibuzone glucuronide, 4-hydroxymethylphenylbutazone glucuronide, 4-hydroxymethyloxyphenbutazone glucuronide, oxyphenbutazone glucuronide, and phenylbutazone glucuronides (two types: O-glucuronide and C-4-glucuroxide) after suxibuzone administration, and oxyphenbutazone glucuronide and phenylbutazone glucuronide after phenylbutazone administration. The conjugates specific to suxibuzone administration, suxibuzone glucuronide, 4-hydroxymethylphenylbutazone glucuronide, and 4-hydroxymethyloxyphenbutazone glucuronide, were excreted in the first 6 hr urine. These findings and the pharmacokinetics of these metabolites in the plasma and urine show that suxibuzone is a prodrug of phenylbutazone.

Disposition and tolerance of suxibuzone in horses

Suxibuzone (SBZ), a nonsteroidal anti-inflammatory drug, was administered to 6 horses at a dose rate of 7.5 mg/kg bwt by intravenous (i.v.) route. Plasma and synovial fluid concentrations of suxibuzone and its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ), were measured simultaneously by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Plasma SBZ concentrations rapidly decreased and were not detectable beyond 20 min after treatment. The parent drug was not detected in any synovial fluid samples. Average maximum plasma concentrations of PBZ (16.43 microg/ml) and OPBZ (2.37 microg/ml) were attained at 0.76 and 7.17 h, respectively. The mean residence time (MRT) of PBZ was 6.96 h in plasma. Oxyphenbutazone plasma concentrations were below those reached by phenylbutazone during the first 12 h after suxibuzone administration, even though its values were detectable for at least 24 h (MRT = 10.65 h). Plasma concentrations of PBZ and OPBZ exceeding EC50 and IC50 of TXB2 and PGE2 were reached by at least 12 h. Synovial fluid concentrations of PBZ and OPBZ were 2.87+/-0.37 microg/ml and 0.97+/-0.08 microg/ml at 9 h after suxibuzone administration and exceeded IC50 of PGE2 for at least this time. In the present study, suxibuzone was well tolerated following i.v. injection.

Effects of top-dress formulations of suxibuzone and phenylbutazone on development of gastric ulcers in horses

Eighteen mature, healthy horses were divided into three groups (six per group) receiving either no treatment, 15 consecutive days of phenylbutazone (PBZ), or 15 consecutive days of suxibuzone (SBZ) at recommended label doses. Horses underwent endoscopy before and after the treatment period and were assigned gastric ulcer scores. Gastric ulcer number and severity scores were similar across treatment groups. These findings suggest that when administered at the recommended label dose for 15 days, neither PBZ nor SBZ causes an increase in the number or severity of gastric ulcers over what would be expected with traditional stabling and intermittent feeding patterns. Also, PBZ-treated horses did not have more severe gastric ulcers than SBZ-treated horses, indicating that SBZ does not appear to offer an advantage over PBZ in preventing gastric ulcers when used at recommended label doses. However, ulcers in other regions of the gastrointestinal tract (e.g., right dorsal colon, duodenum) were not evaluated in horses in this study.

Pharmacokinetics and bioequivalence of two suxibuzone oral dosage forms in horses

A disposition and bioequivalence study with a suxibuzone granulated and a suxibuzone paste oral formulation was performed in horses. Suxibuzone (SBZ) is a nonsteroidal anti-inflammatory drug, which was administered to horses (n = 6) at a dosage of 19 mg/kg bwt by the oral route (p.o.) in a two period cross-over design. Suxibuzone is very rapidly transformed into its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ). Therefore plasma and synovial fluid concentrations of SBZ, PBZ and OPBZ were simultaneously measured by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Suxibuzone could not be detected in any plasma and synovial fluid samples (< 0.04 microgram/mL). Plasma PBZ and OPBZ concentrations were detected between 30 min and 72 h after granulate and paste administration. Mean plasma concentration of PBZ peaked at 5 h (34.5 +/- 6.7 micrograms/mL) and at 7 h (38.8 +/- 8.4 micrograms/mL), and mean area under the concentration-time curve (AUC0-->LOQ) was 608.0 +/- 162.2 micrograms.h/mL and 656.6 +/- 149.7 micrograms.h/mL after granulate and paste administration, respectively. Mean plasma concentration of OPBZ increased to 5-6.7 micrograms/mL, with the maximum concentration (Cmax) appearing between 9 and 12 h after administration of both formulations. The AUCs0-->LOQ for OPBZ were also similar (141.8 +/- 48.3 micrograms.h/mL granulate vs. 171.4 +/- 45.0 micrograms.h/mL paste). It was concluded that the suxibuzone products were bioequivalent with respect to PBZ. For OPBZ, the 95% confidence intervals of the pharmacokinetic parameters were within the acceptable range of 80-125%. The paste formulation provided greater bioavailability of PBZ and OPBZ.