Oxyphenbutazone metabolite

Oxyphenbutazone (712), y-hydroxyphenylbutazone and kebuzone (715) are metabolites of phenylbutazone in liver. The first cited is an equally potent antiinflammatory agent but slightly less toxic. Compounds (711) and (712) are rarely used as analgesics and antipyretics because of their toxicities. The first one is used in therapy of rheumatoid disorders characterized by a lack of detectable antiglobulin and antinuclear antibodies in the serum. The y-hydroxyphenylbutazone has marked uricosuric activity but little antirheumatic effect. Kebuzone (715) is an antiinflammatory agent still widely used in Europe. 

Competition between drugs for plasma binding sites occurs and is responsible for some of the clinically most important changes in drug distribution. Phenylbutazone and oxyphenbutazone, for example, potentiate the action of warfarin by displacement (A2) and trichloroacetic acid, a major metabolite of chloral hydrate has a similar effect (S12) and is the cause of hemorrhagic complications during coumarin therapy (A2). 

Oxyphenbutazone Oxalid, Tandearil) is the principal uricosuric metabolite of phenylbutazone. It has the same indications and toxicities as phenylbutazone. 

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. 

Oxyphenbutazone is a metabolite of phenylbutazone and is limited in use because of a high incidence of hematopoietic side-effects such as fatal agranulocytosis and aplastic anemia (Bottiger and Westerholm, 1973). 

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. 

Oxyphenbutazone is one of the main metabolites of phenylbutazone and is considered to be more toxic. It is rapidly absorbed from the gastrointestinal tract and slowly metabolized and excreted mainly in urine. The rate of its metabolism varies in different species as reflected by the great variance in half-lives. 

The sulfate of oxyphenbutazone is probably not a major metabolite. It hydrolyses in water at room temperature and since less than 2% of oxyphenbutazone is excreted in 24 hrs (17) this would represent the maximal conversion of oxyphenbutazone to sulfate. 

Bruce el aJL (35) determined oxyphenbutazone and phenylbutazone in plasma and urine by gas-liquid chromatography. While phenylbutazone was determined directly after extraction from blood plasma or urine, oxyphenbutazone was reacted with heptafluorobutyric anhydride prior to gas chromatography. Tanimura et al (36) described a gas-liquid chromatographic method for the determination of phenylbutazone and its metabolites, oxyphenbutazone and y-hydroxyphenylbuta-zone in human and rabbit following administration of phenylbutazone. A modified Herrmann s extraction method has been used and coupled with the gas-liquid chromatographic procedure without derivative formation for phenylbutazone and using trimethylsilylation for the 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-... 

Note. The Federation Equestre Internationale does not permit the use of oxyphenbutazone but allows it to be present as a metabolite of phenylbutazone. The criteria for deciding this question are not set out in the rules, but would include absolute concentrations and concentrations relative to phenylbutazone and its other metabolites. 

Disposition in the Body. Almost completely absorbed after oral administration. It is slowly metabolised by glucuronide conjugation and by hydroxylation it is slowly excreted in the urine, less than 2% of a dose being excreted as unchanged drug and about 1 to 5% as the O-glucuronide conjugate in 24 hours. Oxyphenbutazone is a major metabolite of phenylbutazone. 

Disposition in the Body. Readily absorbed after oral or rectal administration and slowly absorbed after intramuscular injection. The major metabolic reactions are C-glucuronidation at the 4-position of the pyrazolidine ring and 4-hydroxylation of one of the phenyl rings to form the active metabolite, oxyphenbutazone 3-hydroxylation of the butyl side-chain to form 3 -hydroxyphenylbutazone, and formation of 4,3 -dihydroxyphenylbutazone also occur. About 61% of a dose is slowly excreted in the urine over a period of about 21 days, together with up to 27% in the faeces. Of the material excreted in the urine, the 4-C-glucuronide of phenylbutazone accounts for about 40%, free phenylbutazone and free oxyphenbutazone about 1%, 4,3 -dihydroxyphenylbutazone about 6%, 3 -hydroxy-phenylbutazone about 3%, and the remainder consists of the C-glucuronide of 3 -hydroxyphenylbutazone (about 12%), oxyphenbutazone 0-glucuronide and two other metabolites. 

Drugs are known that are only active because they are metabolized to bioactive chemical species. An intrinsically active drug is frequently converted to an active metabolite. Well-known examples are the hydrolysis of aspirin to salicylic acid by esterase enzymes, the cleavage of the ethyl ether group of phenacetin to acetaminophen, the demethylation of imipramine to desipramine, and the oxidation of phenylbutazone to oxyphenbutazone. In some cases the precursor drug and its metabolite are both used therapeutically. 

Oxyphenbutazone, a NSAID (300 to 600 mg/day in divided doses), is indicated in pain and inflammation of arthritis and ankylosing spondylitis. Oxyphenbutazone, a metabolite of phenylbutazone, has analgesic, antipyretic, antiinflammatory, and uricosuric properties. Oxyphenbutazone is absorbed orally, is bound to plasma proteins to the extent of 98%, has a half-life of 50 to 100 hours, is metabolized in the liver, and is excreted by the kidneys. Oxyphenbutazone is contraindicated in patients with known hypersensitivity to phenylbutazone in patients in whom aspirin or other NSAIDs induce symptoms of asthma, urticaria, or rhinitis in patients under age 14 because safety has not been established and in patients... 

Oxyphenbutazone (Tanderil, G27202, XXVIII, R = Bu, R = p-HO CgH4) is a metabolite of phenylbutazone , which it resembles in some of its anti-inflammatory properties. Against ultra-violet erythema in guinea-pigs some workers have found it inactive while others have found that, in a dose of 50 mg/kg, it has an anti-erythemic effect equal to that of 18 mg/kg of phenylbutazone. In formalin oedema of the rat-fbot, oxyphenbutazone is similar in activity to phenylbutazone but in 5-hydroxytryptamine and dextran induced swellings the metabolite is practically inactive. It is 2-3 times as effective as phenylbutazone in the kaolin oedema test . ... 

Active metabolites may have superior pharmacological, pharmacokinetic, and safety profiles compared to their respective parent molecules (Fura, 2006 Fura et al., 2004). As a result, a number of active metabolites have been developed and marketed as drugs with improved profiles relative to their parent molecules. Examples of active metabolites of marketed drugs that have been developed as drugs include acetaminophen, oxyphenbutazone, oxazepam, cetirizine (Zyrtec), fexofenadine (Allegra), and desloratadine (Clarinex). Each of these drugs provides a spedlic benefit over the parent molecule and is superior in one or more of the categories described above. 

Azapropazone " and oxyphenbutazone (the major metabolite of phenylbutazone) probably act similarly. 

Vitamin Bi (thiamine), B2 (riboflavin). Be (pyridoxine), B12 (cyanocobalamine), C (ascorbic acid), E (tocopherols), folic acid, pantothenic acid, K, K2, K3 (menadione), PP factor (nicotinamide), biotin Benzimidazole drugs, bromoisovalerylurea, cardiazol, chlorhexidine, dicoumarol, dulcin, isoniazid, 2-nitrofuran derivatives, parabens (4-hydroxybenzoic acid esters), phenacetin, phenylbutazone (and its metabolite oxyphenbutazone), propipocaine, quercetin, rutin, thiomersal (sodium ethylmercurithiosalicylate)... 

Oxyphenbutazone is used for the treatment of inflammation of the eyes and also is one of the active metabolite of phenylbutazone. 

GLC Determination of Plasma Concentrations of Phenylbutazone and Its Metabolite Oxyphenbutazone J. Pharm. Sci. 63(8) 1234-1239 (1974) CA 81 145584a... 

When metabolized, phenylbutazone yields two hydroxylated derivatives . The first is oxyphenbutazone, the properties of which are described above the second contains an alcoholic hydroxyl group in the butyl side-chain XXVIII, R = (CH2)2.CHOHMe, R = Ph). This compound is devoid of anti-inflammatory activity but has enhanced uricosuric potency. Other derivatives with a modified side-chain show increased uricosuric activity associated with anti-inflammatory action. The most important are the phenylthioethyl analogue (G25671, XXVIII, R = (CHajg-SPh, R = Ph) and its metabolite sulphinpyrazone (Anturan, XXVII, R = CHj)a-SOPh, R = Ph). 

This class of agents is characterized by the l-aryl-3,5-pyrazolidinedione structure. The presence of a proton, which is situated between the two electron-withdrawing carbonyl groups, renders these compounds acidic. The p Ta for phenylbutazone is 4.5. Oxyphenbutazone is a hydroxylated metabolite of phenylbutazone (Figure 13.12). 

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