In HFF and HUVEC cells, allopurinol (0, 10, 100, and 1000 µg/ml; 17 hours) can decrease the expression of HIF-1α and HIF-2α proteins [5]. In a 24-hour period, allopurinol (0, 10, 100, or 1000 µg/ml) diminishes the angiogenic characteristics of HUVEC cells [5].

In mice, allopurinol (39 mg/kg; oral; once daily for 21 days) demonstrates antidepressant effects [3]. In mice, allopurinol (10–400 mg/kg; intraperitoneally) elicits antinociceptive action [4].

Western Blot Analysis[5]
Cell Types: HFF, HUVEC Cell
Tested Concentrations: 0, 10, 100, 1000 µg/ml
Incubation Duration: 17 hrs (hours)
Experimental Results: HIF-1α and HIF-2α protein expression diminished in a dose-dependent manner.

Animal/Disease Models: 20-30 g, male Swiss albino mouse [3]
Doses: 39 mg/kg
Route of Administration: oral; one time/day for 21 days
Experimental Results: diminished immobility time in FST, immobility time was 129.8± 10.5 seconds.

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Animal/Disease Models: 30-40 g, male adult Swiss albino mouse [4]
Doses: 10, 50, 100, 200, 400 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: Dose dependence in tail flick and thermal stimulation Sexual antinociceptive effects plate.

Absorption, Distribution and Excretion
This drug is about 90% absorbed from the gastrointestinal tract. Peak plasma levels normally occur at 1.5 hours and 4.5 hours post-dose for allopurinol and oxipurinol respectively. Following one oral dose of 300 mg of allopurinol, maximum plasma levels of about 3 mcg/mL of allopurinol and 6.5 mcg/mL of oxipurinol were measured.
Approximately 80% of orally ingested allopurinol is found excreted in the urine as various metabolites. About 20% of ingested allopurinol is excreted in the feces.
Allopurinol and oxypurinol are both substrates for the enzyme xanthine oxidase, which is present in the cytoplasm of endothelial cells of capillaries, including sinusoids, with the highest activity demonstrated in the liver and intestinal lining. Tissue concentrations of allopurinol have not yet been reported in humans, however, it is probable that allopurinol and the metabolite oxypurinol would be measured in the highest concentrations in the abovementioned tissues. In animals, allopurinol concentrations are found to reach the highest levels in the blood, liver, intestine and heart, and lowest in the brain and lung tissues.
Since allopurinol and its metabolites are mainly eliminated by the kidney, accumulation of this drug can occur in patients with renal dysfunction or failure, and the dose of allopurinol should, therefore, be reduced. With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of allopurinol is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not be higher than 100 mg. With severe renal impairment (creatinine clearance measured at less than 3 mL/min) a longer interval between doses may be required.
Following oral administration, approximately 80-90% of a dose of allopurinol is absorbed from the GI tract. Peak plasma concentrations of allopurinol are reached 2-6 hours after a usual dose.
Allopurinol is absorbed poorly following rectal administration of the drug as suppositories (in a cocoa butter or polyethylene glycol base). Plasma allopurinol or oxipurinol concentrations have been minimal or undetectable following such rectal administration.
Following oral administration of single 100- or 300-mg dose of allopurinol in healthy adult males in one study, peak plasma allopurinol concentrations of about 0.5 or 1.4 ug/mL, respectively, occurred in about 1-2 hours, while peak oxypurinol (the active metabolite of allopurinol) concentrations of about 2.4 and 6.4 ug/mL, respectively, were reached within about 3-4 hours. In the same study, following iv infusion over 30 minutes of a single 100- or 300-mg dose of allopurinol (as allopurinol sodium), peak plasma concentrations of about 1.6 and 5.1 ug/mL, respectively, occurred in about 30 minutes, while peak oxypurinol concentrations of about 2.2 and 6.2 ug/mL, respectively, were reached within about 4 hours.
Following intravenous administration in six healthy male and female subjects, allopurinol was rapidly eliminated from the systemic circulation primarily via oxidative metabolism to oxypurinol, with no detectable plasma concentration of allopurinol after 5 hours post dosing. Approximately 12% of the allopurinol intravenous dose was excreted unchanged, 76% excreted as oxypurinol, and the remaining dose excreted as riboside conjugates in the urine. The rapid conversion of allopurinol to oxypurinol was not significantly different after repeated allopurinol dosing. ... Oxypurinol was primarily eliminated unchanged in urine by glomerular filtration and tubular reabsorption, with a net renal clearance of about 30 mL/min.
For more Absorption, Distribution and Excretion (Complete) data for Allopurinol (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Allopurinol is rapidly metabolized to the corresponding xanthine analog, oxipurinol (alloxanthine), which is also an inhibitor of xanthine oxidase enzyme. Both allopurinol and oxypurinol inhibit the action of this enzyme. Allopurinol and oxypurinol are also converted by the purine salvage pathway to their respective ribonucleotides. The effect of these ribonucleotides related to the hypouricemic action of allopurinol in humans is not fully elucidated to this date. These metabolites may act to inhibit de novo purine biosynthesis by inhibiting the enzyme, _amidophosphoribosyltransferase_. The ribonucleotides have not been found to be incorporated in DNA.
Allopurinol and allopurinol sodium are rapidly metabolized by xanthine oxidase to oxypurinol, which is pharmacologically active. Rapid metabolism of allopurinol to oxypurinol does not seem to be affected substantially during multiple dosing. Pharmacokinetic parameters (eg, AUC, plasma elimination half-lives) of oxypurinol appear to be similar following oral administration of allopurinol and iv administration of allopurinol sodium.
Both allopurinol and oxypurinol are conjugated and form their respective ribonucleosides.
Allopurinol-1-riboside, a major metabolite of allopurinol, is commonly thought to be directly synthesized by purine nucleoside phosphorylase (PNP) in vivo. As this enzyme is otherwise believed to function in vivo primarily in the direction of nucleoside breakdown, we have determined by high performance liquid chromatography and a conventional chromatographic method the urinary metabolites of allopurinol in a child deficient of PNP. In this patient approximately 40% of urinary allopurinol metabolites consisted of allopurinol-1-riboside, thus proving the possibility of indirect formation of allopurinol-1-riboside via allopurinol-1-ribotide in vivo, catalysed by hypoxanthine guanine phosphoribosyltransferase (HGPRT) and a phosphatase.
... The major and active metabolite, oxypurinol, is detected in the circulation within 15 minutes of allopurinol administration. Oxypurinol concentrations are higher than those of the parent drug and accumulation occurs during long term administration. ...Oxypurinol is eliminated by the kidney and has a much longer elimination half-life than allopurinol. Oxypurinol accumulates in patients with renal dysfunction; hence allopurinol dosages should be adjusted in such patients. ...
For more Metabolism/Metabolites (Complete) data for Allopurinol (7 total), please visit the HSDB record page.

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Biological Half-Life
The plasma half-life of allopurinol is 1-2 hours, due to its rapid renal clearance.
The half-lives of allopurinol and oxypurinol are about 1-3 hours and 18-30 hours, respectively, in patients with normal renal function and are increased in patients with renal impairment.
Allopurinol is rapidly cleared from plasma with half-time of 2-3 hr, primarily by conversion to alloxanthine.
Serum half-life of allopurinol is 39 min.

Interactions
Allopurinol inhibits enzymatic inactivation of 6-mercaptopurine by xanthine oxidase. Thus, when allopurinol is used ... with mercaptopurine or azathioprine, dosage of antineoplastic agent must be reduced to one fourth to one third of usual dose.
Many drugs may increase serum urate concentrations, including most diuretics, pyrazinamide, diazoxide, alcohol, and mecamylamine. If these drugs are administered during allopurinol therapy, dosage of allopurinol may need to be increased.
Concomitant administration of allopurinol with cyclophosphamide may increase the incidence of bone marrow depression as compared with cyclophosphamide alone, but the mechanism for this interaction is not known. However, results of a well-controlled study in patients with lymphoma have shown that concomitant use of allopurinol with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine did not increase the incidence of bone marrow depression in these patients.
Incidence of rash occurring after the administration of ampicillin is unusually high in patients receiving allopurinol concomitantly.
For more Interactions (Complete) data for Allopurinol (15 total), please visit the HSDB record page.

[1]. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006 Mar;58(1):87-114.

[2]. Antileishmanial effect of allopurinol. Antimicrob Agents Chemother. 1974;5(5):469-472.

[3]. Evaluation of effect of allopurinol and febuxostat in behavioral model of depression in mice. Indian J Pharmacol. 2013 May-Jun;45(3):244-7.

[4]. Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors. Br J Pharmacol. 2009 Jan;156(1):163-72.

[5]. Dose-dependent effects of allopurinol on human foreskin fibroblast cells and human umbilical vein endothelial cells under hypoxia. PLoS One. 2015 Apr 1;10(4):e0123649.

Therapeutic Uses
Antimetabolites; Antimetabolites, Antineoplastic; Enzyme Inhibitors; Gout Suppressants
Allopurinol is indicated in the management of patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy). /Included in US product label/
Allopurinol is indicated in the management of patients with leukemia, lymphoma and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels. Treatment with allopurinol should be discontinued when the potential for over production of uric acid is no longer present. /Included in US product label/
Allopurinol is indicated in the management of patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients. Therapy in such patients should be carefully assessed initially and reassessed periodically to determine in each case that treatment is beneficial and that the benefits outweigh the risks. /Included in US product label/
For more Therapeutic Uses (Complete) data for Allopurinol (9 total), please visit the HSDB record page.

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Drug Warnings
Since allopurinol and oxypurinol are distributed into milk, allopurinol should be used with caution in nursing women.
Results of early clinical studies and experience suggested that some allopurinol-induced adverse effects (eg, acute attacks of gout, rash) occurred in more than 1% of patients, but current experience suggests that adverse effects of the drug occur in less than 1% of patients. The reduced incidence in adverse effects observed with more recent experience may have resulted in part from initiating therapy with the drug more gradually and following current prescribing precautions and recommendations.
The most common adverse effect of oral allopurinol is a pruritic maculopapular rash. Dermatitides of the exfoliative, urticarial, erythematous, eczematoid, hemorrhagic, and purpuric types have also occurred. Alopecia, fever, and malaise may also occur alone or in conjunction with dermatitis. In addition, severe furunculoses of the nose, cellulitis, and ichthyosis have been reported. The incidence of rash may be increased in patients with renal insufficiency. Skin reactions may be delayed and have been reported to occur as long as 2 years after initiating allopurinol therapy. Rarely, skin rash may be followed by severe hypersensitivity reactions which may sometimes be fatal. Some patients who have developed severe dermatitis have also developed cataracts (including a case of toxic cataracts), but the exact relationship between allopurinol and cataracts has not been established. Pruritus, onycholysis, and lichen planus have also occurred rarely in patients receiving allopurinol. Facial edema, sweating, and skin edema have also occurred rarely, but a causal relationship to the drug has not been established.
Local injection site reactions have been reported in patients receiving allopurinol sodium iv.
For more Drug Warnings (Complete) data for Allopurinol (28 total), please visit the HSDB record page.

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Pharmacodynamics
Allopurinol decreases the production of uric acid by stopping the biochemical reactions that precede its formation. This process decreases urate and relieves the symptoms of gout, which may include painful tophi, joint pain, inflammation, redness, decreased range of motion, and swelling.

C5H4N4O

136.11146

136.038

315-30-0

Allopurinol sodium;17795-21-0;Allopurinol-d2;916979-34-5

135401907

White to off-white solid powder

1.7±0.1 g/cm3

290.8ºC at 760 mmHg

350 ºC

129.7ºC

1.816

-1.46

2

3

0

10

190

0

OFCNXPDARWKPPY-UHFFFAOYSA-N

InChI=1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)

1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one

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 : ~14 mg/mL (~102.86 mM)
H2O : ~1 mg/mL (~7.35 mM)

Solubility in Formulation 1: ≥ 3.33 mg/mL (24.47 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 33.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 3.33 mg/mL (24.47 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 33.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: ≥ 0.61 mg/mL (4.48 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 6.1 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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 (Please use freshly prepared in vivo formulations for optimal results.)