The inhibitory effect of phenylbutazone on COX-1 and COX-2 is minimal [3].

Absorption, Distribution and Excretion
Nonsteroidal anti-inflammatory drugs are 95% bound to plasma protein, especially albumin. With extensive protein binding, there is a small volume of distribution (0.10-0.17 L/kg). The pKa for nonsteroidal anti-inflammatory drugs ranges from 3.5 to 5.2.
Phenylbutazone appears to be rapidly and completely absorbed from the Gl tract. Following oral administration of a single 300 mg dose of phenylbutazone to healthy fasting men, peak plasma phenylbutazone concentrations averaging 43.3 ug/mL are reached within 2.5 hours.
It is recommended that many drugs be taken with or after meals. Recently, however, food intake has been shown to alter significantly the rate and/or extent of absorption of many drugs. Such alterations may induce important changes in the clinical activity of these drugs. Enteric-coated phenylbutazone is recommended to be taken with food to minimize possible gastro-intestinal side-effects. The results of this study demonstrate that while food delays the onset of absorption from this formulation by 4-5 hr, it has no significant effect on the peak concentration or area under the curve. Thus, some effect on fluctuation in plasma levels at steady-state would be expected, but the mean concentration over the recommended dosage interval would remain the same. Treatment efficacy should therefore be unaffected by food but the tolerability may be improved.
Phenylbutazone is almost completely absorbed after oral administration. A large fraction of the drug in plasma is bound to proteins, and the drug has a small volume of distribution. Phenylbutazone is eliminated by metabolism, only 1% being excreted unchanged in the urine. Approximately 10% of a single dose of phenylbutazone is excreted in bile as metabolites. About 60% of the urinary metabolites have been identified. A novel type of drug metabolite in man, the C-glucuronide, is formed by direct coupling of the pyrazolidine ring of phenylbutazone to glucuronic acid via a C-C bond. Phenylbutazone is oxidised in a phenyl ring or in the side chain to hydroxylated metabolites, which may undergo subsequent O-glucuronidation. After a single dose, C-glucuronidation seems to be the dominant reaction, while oxidation becomes increasingly important after repeated administration. Due to different pharmacokinetic properties of the metabolites, the C-glucuronides are detected in highest concentrations in the urine, while the pharmacologically active compounds oxyphenbutazone and gamma-hydroxyphenbutazone predominate in plasma. The biological (elimination) half-life of phenylbutazone in man is long, with a mean of about 70 hours, and exhibits large interindividual and intraindividual variation. The interindividual variation is largely due to genetic factors.
For more Absorption, Distribution and Excretion (Complete) data for Phenylbutazone (14 total), please visit the HSDB record page.

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Metabolism / Metabolites
Phenylbutazone is metabolized in the liver. Phenylbutazone is oxidized to oxyphenbutazone, gamma-hydroxyphenylbutazone, beta-hydroxyphenylbutazone, gamma-ketophenylbutazone, and p,gamma-dihydroxyphenylbutazone. Glucuronide conjugates of phenylbutazone and its metabolites are also formed. In a multiple-dose study in patients with rheumatoid arthritis, plasma concentrations of total oxyphenbutazone decreased with increasing phenylbutazone dose, suggesting that increased chronic doses of phenylbutazone might stimulate elimination of oxyphenbutazone or inhibit oxyphenbutazone formation. Plasma concentrations of gamma-hydroxyphenylbutazone increased proportionally with phenylbutazone dose and showed large interindividual variations.
Major metabolites that have been identified include oxyphenbutazone (ring hydroxylation), Y-hydroxyphenylbutazone (side-chain hydroxylation) Y-hydroxyoxyphenbutazone (dihydroxy metabolite), and 4-hydroxyphenylbutazone. In rats and horses, Y-hydroxyphenylbutazone represents a major (approximately 35%) metabolite and exists in two interchangeable forms; the lactone and the straight-chain forms. The production of the lactone form of Y-phenylbutazone requires cleavage of one of the amide bonds. The formation of this lactone isomer has been shown to be an insignificant reaction in humans. Additional, but apparently minor, products of phenylbutazone oxidation include B-hydroxy- and Y-keto-derivatives of the parent compound.
Phenylbutazone exists in solution in three forms--a diketo, an enol, and a mesomeric anion form. In solution, it exists primarily in the diketo form, and conversion between the forms is slow. These transformations probably contribute to its chemical instability and the ability of the cyclooxygenase system to generate the 4-hydroxphenylbutazone metabolite by a peroxide-dependent cooxygenation reaction.
In addition to the primary metabolites, glucuronide/sulfate conjugates of these primary metabolites have been detected in varying proportions. No glucuronide metabolites have been reported in horses; in rats, approximately 35%-40% of the metabolites are excreted in the urine as conjugated metabolites; in humans, conjugates represent about 50% of urinary metabolites.
... A novel type of drug metabolite in man, the C-glucuronide, is formed by direct coupling of the pyrazolidine ring of phenylbutazone to glucuronic acid via a C-C bond. Phenylbutazone is oxidised in a phenyl ring or in the side chain to hydroxylated metabolites, which may undergo subsequent O-glucuronidation. After a single dose, C-glucuronidation seems to be the dominant reaction, while oxidation becomes increasingly important after repeated administration. Due to different pharmacokinetic properties of the metabolites, the C-glucuronides are detected in highest concentrations in the urine, while the pharmacologically active compounds oxyphenbutazone and gamma-hydroxyphenbutazone predominate in plasma. ...

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Biological Half-Life
Biological half-life of phenylbutazone in plasma was about 6 hr in dogs, 5 hr in guinea-pigs and 3 hr in rabbits.
Biological half-life of phenylbutazone in plasma is 72 hours.
The plasma half-lives of phenylbutazone and oxyphenbutazone (a metabolite) have been reported to be 50-100 hours with large interindividual and intraindividual variations. The plasma half-life of phenylbutazone has been reported to be shorter in children than in adults and in one study was reported to be about 40 hours in children 1-7 years of age. It was suggested that this may result from enhanced cytochrome p450 enzyme activity in children or a greater liver to body weight ratio in children than in adults. Plasma half-lives of phenylbutazone may be somewhat longer in geriatric patients than in younger adults. Age related biologic and physiologic changes (eg, decreased liver and renal function, decreased serum albumin concentration) may be responsible for altered elimination of the drug in geriatric patients. In patients with severely impaired liver function, plasma phenylbutazone half-lives up to 149 hours have been reported.
After administration of a single dose to humans, the plasma concentration of unaltered drug is characterized by an early maximum of 36 ug/mL at 3 hours and by slow decay between 7 and 336 hours, corresponding to an elimination half-life of 88 hours.

Interactions
Because phenylbutazone and oxyphenbutazone (a metabolite) are highly protein bound, they could be displaced from binding sites by, or they could displace from binding sites, other protein bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Patients receiving phenylbutazone with any of these drugs should be observed for adverse effects.
As microsomal enzyme inducers, phenylbutazone and oxyphenbutazone (a metabolite) may accelerate the metabolism of drugs that are affected by this system. Conversely, the metabolism of phenylbutazone may be enhanced and the plasma half-life shortened by concomitant administration of other agents such as barbiturates, promethazine, chlorpheniramine, rifampin, or corticosteroids, which also induce hepatic microsomal enzymes. ... Phenylbutazone may enhance the metabolism of digitoxin (presumably by induction of hepatic microsomal enzymes), resulting in decreased digitoxin plasma concentrations and half-life. ... Phenylbutazone may also enhance the metabolism of aminopyrine, hexobarbital, or corticosteroids.
Administration of phenylbutazone with warfarin or other coumarin or indandione derivative anticoagulants has resulted in increased concentrations of free anticoagulant and an increased risk of serious hemorrhage. Hypoprothrombinemia occurs in almost all patients treated with warfarin and phenylbutazone, usually within the first week and as early as the first day after the initiation of concurrent therapy. This effect has been attributed to displacement of anticoagulants from protein binding sites by phenylbutazone and/or its metabolite, oxyphenbutazone; in addition, phenylbutazone appears to inhibit metabolism of the pharmacologically active S-isomer of warfarin. Phenylbutazone does not affect prothrombin time when administered alone. The ulcerogenic potential of phenylbutazone and the effect of the drug on platelet function further contribute to the hazard of concomitant therapy with any anticoagulant or thrombolytic agent (eg, streptokinase).
Phenylbutazone may potentiate the hypoglycemic effects of acetohexamide, tolbutamide, and other sulfonylureas, possibly through competition for protein binding sites or for urinary excretion. Phenylbutazone has been shown to inhibit the metabolism of tolbutamide, possibly by stimulating a cytochrome P450 like enzyme system that has a low metabolic activity for tolbutamide hydroxylation, and to decrease the renal excretion of hydroxyhexamide (the active metabolite of acetohexamide). Phenylbutazone may also potentiate the hypoglycemic effect of insulin.
For more Interactions (Complete) data for Phenylbutazone (20 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 245 mg/kg
LD50 Rat ip 142 mg/kg
LD50 Rat sc 230 mg/kg
LD50 Rat iv 100 mg/kg
For more Non-Human Toxicity Values (Complete) data for Phenylbutazone (17 total), please visit the HSDB record page.

[1]. Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone. Requirement for peroxidative metabolism. Mol Pharmacol. 1985 Jan;27(1):109-14.

[2]. Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy. Sci Rep. 2016 Apr 29;6:25317.

[3]. COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis. Pharmacol Res. 2005 Oct;52(4):302-6.

Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal
Phenylbutazone became available for use in humans for the treatment of rheumatoid arthritis and gout in 1949. However, it is no longer approved, and thus not marketed, for any human use in the United States. This is because some patients treated with phenylbutazone have experienced severe toxic reactions, and other effective, less toxic drugs are available to treat the same conditions Phenylbutazone is known to induce blood dyscrasias, including aplastic anemia, leukopenia, agranulocytosis, thrombocytopenia and deaths. Hypersensitivity reactions of the serum-sickness type have also been reported. In addition, phenylbutazone is a carcinogen, as determined by the National Toxicology Program.
MEDICATION (Vet): For relief of inflammatory conditions associated with the musculoskeletal system in horses. /Included in US product label/
MEDICATION (Vet): Used in vet medicine as analgesic, antipyretic and an anti-inflammatory agent.
For more Therapeutic Uses (Complete) data for Phenylbutazone (10 total), please visit the HSDB record page.

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Drug Warnings
Stop medication at the first sign of gastrointestinal upset, jaundice, or blood dyscrasia. Authenticated cases of agranulocytosis associated with the drug have occurred in man. To guard against this possibility, conduct routine blood counts at weekly intervals of two weeks thereafter. Any significant fall in the total white count, relative decrease in granulocytes, or black or tarry stools, should be regarded as a signal for immediate cessation of therapy and institution of appropriate counter measures. In the treatment of inflammatory conditions associated with infections, specific anti-infective therapy is required.
Treated animals should not be slaughtered for food purposes. Parenteral injections should be made intravenously only; do not inject subcutaneously or intramuscularly. Use with caution in patients who have a history of drug allergy.
The use of phenylbutazone in patients receiving thrombolytic therapy or long-term anticoagulant therapy, therefore, constitutes a serious risk and should be avoided.
Any substantial change in total leukocyte count, relative decrease in granulocytes, appearance of immature blood cells, or a fall in hematocrit or platelet count are indications for immediate discontinuation of phenylbutazone and a complete hematologic evaluation. Hematologic toxicity may occur shortly after initiation of therapy or after prolonged treatment, it may develop abruptly or gradually, and it may become apparent days or weeks following discontinuance of the drug.
For more Drug Warnings (Complete) data for Phenylbutazone (31 total), please visit the HSDB record page.

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Pharmacodynamics
Phenylbutazone is a synthetic, pyrazolone derivative. It is a nonhormonal anti-inflammatory, antipyretic compound useful in the management of inflammatory conditions. The apparent analgesic effect is probably related mainly to the compound's anti-inflammatory properties and arise from its ability to reduce production of prostaglandin H and prostacyclin. Prostaglandins act on a variety of cells such as vascular smooth muscle cells causing constriction or dilation, on platelets causing aggregation or disaggregation and on spinal neurons causing pain. Prostacylcin causes vascular constriction platelet disaggregation

C19H20N2O2

308.3743

184.984

50-33-9

Phenylbutazone(diphenyl-d10);1219794-69-0;Phenylbutazone-13C12;1325559-13-4;Phenylbutazone-d9;1189479-75-1

4781

White to off-white solid powder

1.5±0.1 g/cm3

240.4±23.0 °C at 760 mmHg

104-107 °C

99.2±22.6 °C

0.0±0.5 mmHg at 25°C

1.613

2.76

0

2

5

23

389

0

VYMDGNCVAMGZFE-UHFFFAOYSA-N

InChI=1S/C19H20N2O2/c1-2-3-14-17-18(22)20(15-10-6-4-7-11-15)21(19(17)23)16-12-8-5-9-13-16/h4-13,17H,2-3,14H2,1H3

4-butyl-1,2-diphenylpyrazolidine-3,5-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~324.29 mM)
H2O : ~0.67 mg/mL (~2.17 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)