Phenylbutazone, pharmacokinetics

Aarbakke J. Clinical pharmacokinetics of phenylbutazone. Clin Pharmacokinet 1978 3(5) 369-380. 

It is a metabolite of phenylbutazone and having similar pharmacodynamic and pharmacokinetic properties and similar therapeutic uses. 

Detailed pharmacokinetic studies on phenylbutazone revealed that the principal metabolite consists of a phenol from the hydroxylation of one of the aromatic rings (97-8). The finding that this compound was more potent than the parent drug led to its introduction as a drug in its own right. Coupling of the benzenediazonium... 

The most serious interactions with warfarin are those that increase the anticoagulant effect and the risk of bleeding. The most dangerous of these interactions are the pharmacokinetic interactions with the pyrazolones phenylbutazone and... 

Even more subtle effects arise for drug interactions of a non-chiral drug with a chiral one. Phenylbutazone is not chiral in itself but it can interact with a chiral drug, warfarin, to change the activity of the latter. Phenylbutazone inhibits the oxidative metabolism of the (S)-(-) form of warfarin, (which is five times more potent than the (/ )-(+) form) and thereby decreases its clearance. Conversely, phenylbutazone induces the enzymatic reduction of the (/ ) form thus increasing the clearance.93 Analysis of total warfarin may indicate little departure from normal pharmacokinetics, but the distribution of eutomer and distomer will have changed markedly. 

The procedure was described as accurate and sufficiently sensitive for use in routine clinical assay and the estimation of the pharmacokinetic parameters of phenylbutazone and its metabolites. 

Pharmacokinetics Phenylbutazone is rapidly and completely absorbed after oral or rectal administration. Oxyphenbutazone is an active metabolite and contributes to the activity of the parent drug. Like most of the other NSAIDs, phenylbutazone is extensively bound to plasma proteins. This property causes displace-... 

The area of clinical pharmacology that first directed attention to the consequences of stereoisomerism on therapeutic and pharmacokinetics was that of drug interactions, particularly those of the anticoagulant warfarin. Not only may drug interactions be stereoselective, but there is a potential for one stereoisomer to alter the pharmacokinetics and pharmacodynamics of the other. A classical example is the interaction with achiral phenylbutazone, which inhibits the metabolism of active 5-warfarin but stimulates the metabolism of the less active R isomer. Other stereoselective drug interactions include the induced elimination of misoni-dazole by phenytoin. Phenytoin enhances the clearance of (4—)-misonidazole by 56%o, which is higher than the increase in clearance of 33%o noted for (—)-misonidazole. 

Maitho, T.E. Lees, P. Taylor, J.B. Absorption and pharmacokinetics of phenylbutazone in welsh mountain ponies. J. Vet. Pharmacol Ther. 1986, 9, 26-39. 

Schulz E, Koch K, Schmidt FH. [Potentiation of the hypoglycemic effect of sulfonylurea derivatives by drugs. II. Pharmacokinetics and metabolism of glibenclamide (HB 419) in presence of phenylbutazone.] Eur J Clin Pharmacol 1971 4(l) 32-7. 

The nse of high-speed LC-MS-MS with a heated-nebrrhzer atmospheric-pressnre chemical ionization (APCI) interface in a bioassay for phenylbutazone and its metabolites in eqnine urine and plasma, described by Covey et al. [1] in 1986, can be considered as a breakthrough in LC-MS. Phenylbutazone, hydroxy-phenylbutazone, and oxy-phenylbutazone were separated on a 33x4.6-mm-ID colunm packed with 3-pm particles in only 1 min. SRM of fottr product iorts per analyte was apphed. The results for phenylbutazone in a 60-sample, 48-h phenylbntazone pharmacokinetic study are shown in Figrtre 11.1. A set of 5 standards, 11 plasma samples, and 11 urine samples were analysed in duplo within 60 min [1]. 

Figure 11.1 Ion current of the phenylbutazone daughter ions for a 60-sample, 48-h pharmacokinetic study in the horse using high-speed LC-MS-MS. Reprinted from [1] with permission, 1986, American Chemical Society.

Pharmacokinetics of intravenous and intragastric cimetidine in horses. I. Effects of intravenous cimetidine on pharmacokinetics of intravenous phenylbutazone. Journal of Veterinary Pharmacology and Therapeutics 20 355-361... 

In general, NSAIDs share a number of different pharmacokinetic properties. For example, most, but not all, have relatively short plasma half-lives. Meclofenamic acid and ketoprofen, for example, have plasma half-lives of l-2h in the horse (Owens et al 1995a, Snow et al 1981). Phenylbutazone has a more variable plasma half-life but it is usually determined to be less than 8h (Lees Higgins 1985). In contrast, the plasma half-life of carprofen is between 18 and 21 h in the horse (Lees et al 1994, McKellar et al 1991). 

In the presence of inflammation, the pharmacokinetics of NSAIDs may be altered. For example, in one study comparing with normal horses, the clearance and of phenylbutazone were increased in horses with experimentally induced inflammatory loci (Mills et al 1996). Horses with experimentally induced inflammation also cleared ketoprofen faster than normal horses (Owens et al 1995a). 

Phenylbutazone is an enolic acid derivative in the pyrazolone class of NSAIDs. The pharmacokinetics and pharmacodynamics of phenylbutazone, the most commonly prescribed NSAID for use in horses, have been well studied. In the horse, the plasma half-life of phenylbutazone ranges from 3 to 8 h. The plasma half-life in an individual horse is dependent on the dose administered and the metabolic capacity of that animal. For example, when a single dose of phenylbutazone was administered i.v. at a dose rate of 4.4 mg/kg, the plasma half-life was 5.5 h (Lees et al 1987b). In a... 

Eltenac is an acetic acid derivative that appears to be effective and relatively safe when used in horses (Prugner et al 1991). The pharmacokinetics of eltenac have been examined in several studies. It has a short plasma half-life of 1.7-3 h and a small Vd (approximately 0.21/kg) (Dyke et al 1998, Prugner et al 1991). There was no indication of accumulation in the plasma after 4 days of repeated i.v. administrations (0.5 mg/kg), unlike phenylbutazone (Dyke et al 1998). 

Galbraith L A, McKellar Q A 1996 Protein binding and in vitro serum thromboxane B2 inhibition by flunixin meglumine and meclofenamic acid in dog, goat and horse blood. Research in Veterinary Science 61 78-81 Gerring E L, Lees P, Taylor J B 1981 Pharmacokinetics of phenylbutazone and Its metabolites in the horse. Equine Veterinary Journal 13 152-157 Glaser K, Sung M L, O Neill K et al 1995 Etodolac... 

Lees P, Maitho T E, Taylor J B O 1985 Pharmacokinetics of phenylbutazone in two age groups of ponies a preliminary study. Veterinary Record 116 229-232 Lees R Taylor J B O, Higgins A J et al 1986 Phenylbutazone and oxyphenbutazone distribution Into tissue fluids in the horse. Journal of Veterinary Pharmacology and Therapeutics 9 204-212... 

Lees P, Taylor J B, Maitho T E et al 1987b Metabolism, excretion, pharmacokinetics and tissue residues of phenylbutazone In the horse. Cornell Veterinarian 77 192-211... 

Pharmacokinetics of ketoprofen in healthy horses and horses with acute synovitis. Journal of Veterinary Pharmacology and Therapeutics 18 187-195 Owens J G, Kamerling S G, Stanton S R et al 1995b Effects of ketoprofen and phenylbutazone on chronic hoof pain and lameness in the horse. Equine Veterinary Journal 27 296-300... 

Snow D H, Baxter R Whiting B 1981 The pharmacokinetics of meclofenamic acid in the horse. Journai of Veterinary Pharmacoiogy and Therapeutics 4 147-156 Soma L R, Gailis D E, Davis W L et ai 1983 Phenylbutazone kinetics and metabolic concentrations in the horse after five days of administration. American Journai of Veterinary Research 44 2104-2109 Soma L R, Behrend E N, Rudy J A et al 1988 Disposition and excretion of fiunixin meglumine in horses. American Journal of Veterinary Research 49 1894-1898 Soraci A, Benoit E, Jaussaud P et al 1995 Enantioselective glucuronidation and subsequent biliary excretion of carprofen in horses. American Journal of Veterinary Research 56 358-361... 

Toutain P L, Autefage A, Legrand C et al 1994 Plasma concentrations and therapeutic efficacy of phenylbutazone and fiunixin meglumine in the horse pharmacokinetic/pharmacodynamic modeling. Journal of Veterinary Pharmacology and Therapeutics 17 459-469... 

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