Phenylbutazone, metabolism

Tobin T, Blake J W, Valentine R W 1977 Drug interactions in the horse effects of chloramphenicol, quinidine and oxyphenbutazone on phenylbutazone metabolism. American Journal of Veterinary Research 38 123-127... 

Studies on Phenylbutazone Metabolism Using a Stable Isotope Tracer Technique. Measurement of Plasma Concentration of Phenylbutazone by Mass Fragmentography Koenshu - lyo Masu Kenkyukai 3 63-68 (1978) CA 92 157424p... 

Pyrazolone-type dmgs, such as phenylbutazone and sulfinpyrazone, ate metabolized in the Hver by microsomal enzymes, forming glucutonide metabohtes that ate easily excreted because of enhanced water solubility. 

Although some authors propose that an enolizable /3-dicarbonyl system is essential for inflammatory activity, two analogues in which this hydrogen atom at carbon 4 has been substituted, suxibuzone (717) and pipebuzone (718), are used as antiinflammatory agents, and the latter also possesses antipyretic and analgesic properties. However, these compounds are probably not active per se and their activity is due to metabolism to phenylbutazone. 

Table VI lists several drugs Inducing hepatic microsomal enzymes (5). These enzymes can metabolize the drug as well as other substrates. Barbiturates, grlseofulvln, and glutethlmlde Induce enzymes which metabolize coumarln and phenlndlone derivatives and thus reduce their anticoagulant activity. Dlphenylhydantoln and phenylbutazone stimulate cortisol hydroxylase activity and Increase the urinary excretion of B-hydroxy cortisol and decrease the concentration of cortisol In the plasma.

Peroxyl radicals are the species that propagate autoxidation of the unsaturated fatty acid residues of phospholipids (50). In addition, peroxyl radicals are intermediates in the metabolism of certain drugs such as phenylbutazone (51). Epoxidation of BP-7,8-dihydrodiol has been detected during lipid peroxidation induced in rat liver microsomes by ascorbate or NADPH and during the peroxidatic oxidation of phenylbutazone (52,53). These findings suggest that peroxyl radical-mediated epoxidation of BP-7,8-dihydrodiol is general and may serve as the prototype for similar epoxidations of other olefins in a variety of biochemical systems. In addition, peroxyl radical-dependent epoxidation of BP-7,8-dihydrodiol exhibits the same stereochemistry as the arachidonic acid-stimulated epoxidation by ram seminal vesicle microsomes. This not only provides additional... 

When individuals were administered 800 mg. per day of phenylbutazone (Butazolidin) for 14 days or more, each developed a characteristic plasma level.39 For 60 subjects this level ranged from 60 to 150 mg. per liter and was constant from day to day for individuals. It was concluded that the rate at which the drug was metabolized under the conditions used varied from 17 to 35 per cent per day for different individuals. It is interesting that the "biological half-life" of this substance varies from species to species3 hours for rabbits, 6 hours for dogs and rats, 72 hours for man. It is also clear from the above that its rate of disappearance varies widely for individual human subjects. 

A similar metabolic pathway has been characterized in the rat for phenylbutazone, whose y-hydroxylated metabolite (11.159) slowly attained equilibrium with its tautomeric 6-lactone [168], The two tautomers together represented one-third of the dose in 48 h urine. 

Phenylbutazone is metabolized by the liver at a rate of about 15-25% per day (B33), but plasma levels do not increase proportionately with increasing doses of the drug. The work of Burns et al. (B33) indicates that above a certain level plasma phenylbutazone concentrations plateau. The concentration at which this occurs varies among individuals and is probably a reflection of the level at which saturation of high-affinity plasma protein binding sites occurs. 

The plasma concentration of phenylbutazone is not proportional to the dosage, probably owing to genetic variations in its rate of metabolism (V8, W9), but in any individual patient on a constant dosage the plasma concentration remains constant over prolonged periods. 

L7. Levi, A. J., Sherlock, S., and Walker, D., Phenylbutazone and isoniazid metabolism in patients with liver disease in relation to previous di-ug therapy. Ixincet... 

Phenylbutazone was recognised to potentiate the anticoagulant effect of warfarin as long ago as 1959. As subsequent in vitro studies confirmed that phenylbutazone displaced warfarin from its protein binding site, it was assumed that any non-steroidal antiinflammatory drug (NSAID) would enhance warfarin s anticoagulant effect in this way. However it is now known that the interaction is due instead to a stereoselective inhibition of the metabolism of warfarin. Warfarin is available as a racemic mixture of two enantiomers R and S), and of these the S enantiomer is five times more potent as an anticoagulant. Phenylbutazone inhibits the metabolism of the... 

Phenylbutazone (Butazolidin) is metabolized to oxy-phenbutazone (Phlogistol), and both compounds have all of the activities associated with the NSAIDs. Their use is accompanied by serious adverse reactions, such as anemia, nephritis, renal failure or necrosis, and liver damage. Because of their toxicity, they are prescribed only for the treatment of pain associated with gout or phlebitis or as a last resort for other painful inflammatory diseases resistant to newer and less toxic treatments. Interactions with a large number of other drugs... 

Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short, with an elimination half-life of 4-5 hours, and it is best administered in divided doses. Because of its short half-life, it is the safest sulfonylurea for elderly diabetics. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain drugs (eg, dicumarol, phenylbutazone, some sulfonamides) that inhibit the metabolism of tolbutamide. 

Little information is available regarding tissue distribution or metabolic products of nonsteroidal anti-inflammatory drugs in cattle. The early synthetic compounds were simple derivatives either of salicylic acid such as acetylsalicylic acid and methylsalicylic acid, or of pyrazolone such as metamizole, oxyphenbuta-zone, phenylbutazone, propylphenazone, and suxibuzone. Modern nonsteroidal anti-inflammatory drugs are derivatives either of anthranilic acid such as dido-... 

Following oral treatment, suxibuzone is slowly absorbed from the gastrointestinal tract, but is very rapidly distributed in the body. In all species, suxibuzone was rapidly metabolized to phenylbutazone, which subsequently was metabolized to oxyphenbutazone and -hydroxyphenylbutazone. Animals treated with suxibuzone exhibited lower plasma concentrations of the parent drug than the phenylbutazone metabolite. Available data on phenylbutazone, the principal suxibuzone metabolite, indicated that phenylbutazone has carcinogenic potential for animals. 

The actions of non-steroidal anti-inflammatory drugs appear to be diverse. Phenylbutazone and sulfmpyrzone inhibited several effects of FMLP on PMNs increased adhesiveness, stimulation of the hexosemonophosphate shunt, lysosomal enzyme release, and formation of O These effects were explained by the ability of both phenylbutazone and sulfinpyrazone to inhibit binding of labelled FMLP to PMNs. Both were selective in that neither inhibited responses of PMNs to Csa and neither inhibited the stimulation of the hexose monophosphate shunt by latex or by opsonized Candida. The responses of PMNs to FMLP, including the release of O have also been inhibited by 5,8,11,14 eicosatetraynoic acid, an inhibitor of the metabolism of arachidonic acid h by indomethacin and by... 

The peak plasma concentration is reached 2 h after oral administration. The degree of binding of phenylbutazone to plasma proteins is 98%. The long elimination half-life of phenylbutazone (mean -70 h) exhibits large interindividual and intraindividual variation. It is metabolized in the liver by oxidation and glucuronidation and excreted in the urine and to a lower degree (-25%) in the faeces (Aarbakke, 1978). Oxyphenbutazone is an active metabolite of phenylbutazone. The metabolic pathway of phenylbutazone is shown in Scheme 72. 

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. 

Pond SM, Birkett DJ, Wade DN. Mechanisms of inhibition of tolbutamide metabolism phenylbutazone, oxyphenbu-tazone, sulfaphenazole. Clin Pharmacol Ther 1977 22(5 Pt l) 573-9. 

Organochlorine insecticides are also well-known inducers. Treatment of rats with either DDT or chlordane, for example, will decrease hexobarbital sleeping time and offer protection from the toxic effect of warfarin. Persons exposed to DDT and lindane metabolized antipyrine twice as fast as a group not exposed, whereas those exposed to DDT alone had a reduced half-life for phenylbutazone and increased excretion of 6-hydroxy cortisol. 

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