Phenylbutazone and its metabolites in plasma and urine of thoroughbred horses: population distributions and effects of urinary pH

Abstract

A survey of plasma and urinary concentrations of phenylbutazone and its metabolites in thoroughbred horses racing in Kentucky was carried out. Post-race blood samples from more than 200 horses running at Latonia Racetrack and Keeneland in the Spring of 1983 were analysed. The modal plasma concentration of phenylbutazone was between 1 and 2 micrograms/ml, the mean concentration was 3.5 micrograms/ml and the range was up to 15 micrograms/ml. Oxyphenbutazone had a modal plasma concentration between 1 and 2 micrograms/ml, a mean concentration of 2.07 micrograms/ml and a range of up to 13 micrograms/ml. gamma OH-phenylbutazone had a modal plasma concentration of less than 1 microgram/ml, a mean level of 1.39 micrograms/ml and a range of up to 7.32 micrograms/ml. All plasma concentration frequency distributions were well fitted by log normal distributions. Urinary concentrations of phenylbutazone yielded modal concentrations of less than 1 microgram/ml, a mean urinary concentration of 2.9 micrograms/ml, with a range of up to 30.5 micrograms/ml. This population fitted a log-normal distribution. For oxyphenbutazone the modal concentration was less than 3 micrograms/ml, the mean concentration was 15.26 micrograms/ml, with a range to 81.5 micrograms/ml. The frequency distribution of these samples was apparently bimodal. For gamma OH-phenylbutazone, the modal concentration was less than 4 micrograms/ml, the mean concentration 21.23 micrograms/ml, with a range of up to 122 micrograms/ml. The population frequency distribution for gamma OH-phenylbutazone was indeterminate. Analysis of the pH of these post-race urine samples showed a bimodal frequency distribution. The pH values observed ranged from 4.9 to 8.7, with peaks at about pH 5.25 and 7.25. This bimodal pattern of urinary pH values is consistent with observations made in England and Japan. Urinary pH influenced the concentrations of phenylbutazone, oxyphenbutazone and gamma OH-phenylbutazone found in the urine samples. The concentration of these metabolites found in alkaline urines were from 32 to 225 times greater than those found in acidic urines. Plasma concentrations of phenylbutazone and its metabolites, however, were unaffected by urinary pH. In interlaboratory experiments, horses running at Hollywood Park were dosed with phenylbutazone at about 2 g/1000 lbs 24 and 48 h before racing, and a mean dose of 0.6 g/1000 lbs at 72 h prior to racing. Post-race plasma samples from these horses showed phenylbutazone concentrations ranging from 0.44 to 9.97 micrograms/ml, with a mean concentration of 4.09 micrograms/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

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

“…It is noteworthy that the computed IUC is lower than the LOD (about 50 ng/ml) reported in the literature; and that the urinary concentration of PBZ can be modified dramatically by the urinary pH. It was shown in postrace urine from horses racing in Kentucky that urinary PBZ concentrations can by multiplied by 200 when the pH increases from 4 to 8.5 (Houston et al 1985). As urinary pH does not influence plasma clearance, it is probable that a PBZ IUC of 10 ng/ml is much more conservative for a horse with a basic urine pH than for one with an acid urine pH (see Discussion).…”

“…For a multiple drug administration, the urine to plasma ratio is permanently changing until steady state conditions are reached, when Rss can be constant over a more or less large fraction of the dosing interval. In addition, Rss can be influenced by water diuresis (urine volume) and some physiological factors, such as urine pH (Houston et al 1985). For all these reasons, urine is a less than ideal matrix for controlling a no effect drug level and changing the drug control policy could make urine much less attractive (appropriate) than for controlling drug exposure.…”

Pharmacokinetics of methocarbamol and phenylbutazone in exercised Thoroughbred horses

“…Arguably, the most common drug-drug interaction affecting clearance is competition for metabolic enzymes. With respect to MCBL and PBZ, both compounds are extensively metabolized prior to elimination (Bruce et al, 1971;Gerring et al, 1981;Soma et al, 1983;Houston et al, 1985); however, to the authors' knowledge, the exact metabolic enzymes responsible for metabolism of the two compounds in the horse have yet to be determined. While further study, specifically to determine the metabolic enzymes responsible for metabolism of each, would be prudent to fully describe potential drug-drug interactions, this was beyond the scope of the current study.…”

Direct-injection screening for acidic drugs in plasma and neutral drugs in equine urine by differential-gradient LC–LC coupled MS/MS

“…It has been stated that postadministration blood concentrations of compounds that ionise in aqueous solution, as the acidic drugs do, are more predictable than the corresponding urinary levels [8] and data from several recent equine pharmacokinetic studies [9][10][11][12][13] seems to support that contention. Consequently, we opted to develop a broadbased screen of negative heated nebulizer (−HN) responsive substances using protein-precipitated plasma as our analytical matrix.…”