アロプリノール
概要
説明
Allopurinol is a medication primarily used to decrease high blood uric acid levels. It is specifically used to prevent gout, certain types of kidney stones, and the high uric acid levels that can occur with chemotherapy . Allopurinol is taken orally or intravenously and is classified as a xanthine oxidase inhibitor .
作用機序
Target of Action
Allopurinol primarily targets the enzyme xanthine oxidase . Xanthine oxidase plays a crucial role in the conversion of hypoxanthine to xanthine and xanthine to uric acid, which are key steps in purine metabolism .
Mode of Action
Allopurinol acts as a xanthine oxidase inhibitor . It is a structural analogue of the natural purine base, hypoxanthine . By competitively binding to xanthine oxidase, allopurinol inhibits the conversion of hypoxanthine to xanthine and xanthine to uric acid . This results in increased concentrations of hypoxanthine and xanthine in urine and plasma, and decreased concentrations of uric acid in plasma
科学的研究の応用
Allopurinol has a wide range of scientific research applications:
Chemistry: It is used as a model compound in studies of xanthine oxidase inhibition and purine metabolism.
Biology: Allopurinol is used to study the effects of uric acid reduction on cellular processes and metabolic pathways.
Medicine: It is extensively used in clinical research for the treatment of gout, kidney stones, and hyperuricemia. .
生化学分析
Biochemical Properties
Allopurinol acts on purine catabolism, reducing the production of uric acid without disrupting the biosynthesis of vital purines . It is a structural analogue of the natural purine base, hypoxanthine . It interacts with the enzyme xanthine oxidase, inhibiting the biochemical reactions immediately preceding the formation of uric acid .
Cellular Effects
Allopurinol can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill . More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia .
Molecular Mechanism
Allopurinol is a structural analog of the natural purine base, hypoxanthine. Oxypurinol acts as an inhibitor of xanthine oxidase enzyme .
Temporal Effects in Laboratory Settings
Allopurinol has a half-life of 1.2 ± 0.3 hours, and its active metabolite, oxypurinol, has a half-life of 23.3 ± 6.0 hours . The effects of allopurinol can change over time in laboratory settings, with a significant reduction in state 3 respiration and state 4 respiration observed in treated subjects compared to controls .
Dosage Effects in Animal Models
In dogs, allopurinol is started at a low dose (50-100 mg daily) and the dose is then increased in 100 mg increments approximately every 4 weeks until the target serum uric acid level has been achieved . In dogs with renal impairment, smaller increments (50 mg) should be used and the maximum dose will be lower .
Metabolic Pathways
Allopurinol is almost completely metabolized to oxypurinol within two hours of oral administration, whereas oxypurinol is slowly excreted by the kidneys over 18–30 hours . Allopurinol acts on purine catabolism, reducing the production of uric acid without disrupting the biosynthesis of vital purines .
Transport and Distribution
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 .
Subcellular Localization
The subcellular localization of allopurinol remains controversial and wholly undetermined . It is known that allopurinol and its active metabolite, oxypurinol, are substrates for the enzyme xanthine oxidase, which is present in the cytoplasm of endothelial cells of capillaries .
準備方法
Synthetic Routes and Reaction Conditions: Allopurinol can be synthesized through various methods. One common method involves the cyclization of 4,6-diamino-5-formamidopyrimidine with formic acid to produce 4,6-diamino-5-formamidopyrimidine-2-carboxamide, which is then cyclized to form allopurinol . The reaction conditions typically involve heating and the use of solvents such as water or ethanol.
Industrial Production Methods: In industrial settings, allopurinol is produced using a similar synthetic route but on a larger scale. The process involves the use of high-purity starting materials and stringent quality control measures to ensure the final product meets pharmaceutical standards .
化学反応の分析
Types of Reactions: Allopurinol undergoes various chemical reactions, including oxidation, reduction, and substitution reactions.
Common Reagents and Conditions:
Oxidation: Allopurinol can be oxidized using reagents such as hydrogen peroxide or potassium permanganate under acidic conditions.
Reduction: Reduction of allopurinol can be achieved using reducing agents like sodium borohydride or lithium aluminum hydride.
Substitution: Substitution reactions involving allopurinol typically use halogenating agents like chlorine or bromine under controlled conditions.
Major Products: The major products formed from these reactions include oxypurinol (an oxidation product) and various substituted derivatives depending on the reagents used .
類似化合物との比較
Febuxostat: Another xanthine oxidase inhibitor used to lower uric acid levels.
Probenecid: A uricosuric agent that increases the excretion of uric acid in the urine.
Benzbromarone: Another uricosuric agent that is used to lower uric acid levels but is less commonly used due to potential hepatotoxicity.
Uniqueness of Allopurinol: Allopurinol is unique in its dual action of reducing uric acid production and being metabolized to oxypurinol, which also inhibits xanthine oxidase. This dual action makes it highly effective in managing hyperuricemia and gout .
特性
IUPAC Name |
1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
OFCNXPDARWKPPY-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1=NNC2=C1C(=O)NC=N2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C5H4N4O |
Source
|
| Record name | 4-HYDROXYPYRAZOLO(3,4-D)PYRIMIDINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/20510 | |
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| Record name | allopurinol | |
| Source | Wikipedia | |
| URL | https://en.wikipedia.org/wiki/Allopurinol | |
| Description | Chemical information link to Wikipedia. | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID4022573 |
Source
|
| Record name | Allopurinol | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4022573 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
136.11 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
4-hydroxypyrazolo(3,4-d)pyrimidine is an odorless tasteless white microcrystalline powder. (NTP, 1992), Solid |
Source
|
| Record name | 4-HYDROXYPYRAZOLO(3,4-D)PYRIMIDINE | |
| Source | CAMEO Chemicals | |
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| Record name | Allopurinol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014581 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Solubility |
17.1 [ug/mL] (The mean of the results at pH 7.4), less than 1 mg/mL at 64 °F (NTP, 1992), solubility in water at 37°C is 80.0 mg/dL and is greater in an alkaline solution, Solubility in mg/mL at 25 °C: water 0.48; n-octanol < 0.01; chloroform 0.60; ethanol 0.30; dimethyl sulfoxide 4.6., In water, 569 mg/L at 25 °C, 5.88e+00 g/L |
Source
|
| Record name | SID56424020 | |
| Source | Burnham Center for Chemical Genomics | |
| URL | https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table | |
| Description | Aqueous solubility in buffer at pH 7.4 | |
| Record name | 4-HYDROXYPYRAZOLO(3,4-D)PYRIMIDINE | |
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| Record name | Allopurinol | |
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| Record name | Allopurinol | |
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Mechanism of Action |
Allopurinol is a structural analog of the natural purine base, hypoxanthine. After ingestion, allopurinol is metabolized to its active metabolite, oxypurinol (_alloxanthine_) in the liver, which acts as an inhibitor of xanthine oxidase enzyme. Allopurinol and its active metabolite inhibit xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Inhibition of this enzyme is responsible for the effects of allopurinol. This drug increases the reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis by a process that involves the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). This process results in an increased nucleotide concentration, which causes feedback inhibition of de novo purine synthesis. The end result is decreased urine and serum uric acid concentrations, which decreases the incidence of gout symptoms. Accompanying the reduction of serum uric acid by allopurinol is an increase in the serum and urine concentrations of hypoxanthine and xanthine (due to inhibition of xanthine oxidase). In the absence of allopurinol, regular urinary excretion of oxypurines almost entirely occurs in the form of uric acid. After the ingestion of allopurinol, the contents of excreted urine are hypoxanthine, xanthine, and uric acid. Because each substance has its own individual solubility, the concentration of uric acid in plasma is decreased without exposing the renal tissues to a high load of uric acid, thereby decreasing the risk of crystalluria. By lowering the uric acid concentration in the plasma below its limits of solubility, allopurinol encourages the dissolution of gout tophi. Although the levels of hypoxanthine and xanthine are found to be increased after allopurinol ingestion, the risk of deposition in renal tissues is less than that of uric acid, as they become more soluble and are rapidly excreted by the kidney., Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Oxypurinol, a metabolite of allopurinol, also inhibits xanthine oxidase. By inhibiting xanthine oxidase, allopurinol and its metabolite block conversion of the oxypurines (hypoxanthine and xanthine) to uric acid, thus decreasing serum and urine concentrations of uric acid. The drug differs, therefore, from uricosuric agents which lower serum urate concentrations by promoting urinary excretion of uric acid. Xanthine oxidase concentrations are not altered by long-term administration of the drug., Allopurinol does not directly interfere with purine nucleotide or nucleic acid synthesis. The drug, however, indirectly increases oxypurine and allopurinol ribonucleotide concentrations and decreases phosphoribosylpyrophosphate concentrations, thus decreasing de novo purine biosynthesis by pseudofeedback inhibition. In addition, allopurinol increases the incorporation of hypoxanthine and xanthine into DNA and RNA, thereby further decreasing serum urate concentrations. Allopurinol may produce a deficit of total purines (uric acid and oxypurines) amounting to several hundred mg daily., Accompanying the decrease in uric acid produced by allopurinol is an increase in serum and urine concentrations of hypoxanthine and xanthine. Plasma concentrations of these oxypurines do not, however, rise commensurately with the fall in serum urate concentrations and are often 20-30% less than would be expected in view of urate concentrations prior to allopurinol therapy. This discrepancy occurs because renal clearance of the oxypurines is at least 10 times greater than that of uric acid. In addition, normal urinary purine output is almost exclusively uric acid, but after treatment with allopurinol, it is composed of uric acid, xanthine, and hypoxanthine, each having independent solubility. Thus, the risk of crystalluria is reduced. Alkalinization of the urine increases the solubility of the purines, further minimizing the risk of crystalluria. Decreased tubular transport of uric acid also results in increased renal reabsorption of calcium and decreased calcium excretion., Allopurinol also interferes with de novo pyrimidine nucleotide synthesis by inhibiting orotidine 5'-phosphate decarboxylase. Secondary orotic aciduria and orotidinuria result. Orotic acid is highly insoluble and could form a heavy sediment of urinary crystals; however, the increased excretion of orotic acid and orotidine rarely exceeds 10% of the total pyrimidines synthesized by the body. In addition, enhanced conversion of uridine to uridine 5'-monophosphate usually occurs and, therefore, this partial inhibition of pyrimidine synthesis is considered innocuous., Allopurinol may also inhibit hepatic microsomal enzymes. Allopurinol is not cytotoxic and has no effect on transplantable tumors. The drug has no analgesic, anti-inflammatory, or uricosuric activity. |
Source
|
| Record name | Allopurinol | |
| Source | DrugBank | |
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Color/Form |
FLUFFY WHITE TO OFF-WHITE POWDER, Crystals | |
CAS No. |
315-30-0, 184789-03-5, 691008-24-9 |
Source
|
| Record name | 4-HYDROXYPYRAZOLO(3,4-D)PYRIMIDINE | |
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| Record name | 2,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one | |
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| Record name | 4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1,5-dihydro-, radical ion(1+) | |
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Melting Point |
greater than 662 °F (NTP, 1992), >300, 350 °C |
Source
|
| Record name | 4-HYDROXYPYRAZOLO(3,4-D)PYRIMIDINE | |
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| Record name | Allopurinol | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014581 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Retrosynthesis Analysis
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| Precursor scoring | Relevance Heuristic |
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Feasible Synthetic Routes
Q1: How does Allopurinol exert its urate-lowering effect?
A: Allopurinol is a purine analog that acts as a xanthine oxidase inhibitor. Xanthine oxidase is the enzyme responsible for the final two steps in the metabolic breakdown of purines to uric acid. By inhibiting xanthine oxidase, allopurinol reduces the production of uric acid, thereby lowering its concentration in the blood. []
Q2: What is the active metabolite of Allopurinol and how does it contribute to urate lowering?
A: Allopurinol is metabolized in the liver to oxypurinol, which also acts as a xanthine oxidase inhibitor. Oxypurinol has a much longer half-life than allopurinol, contributing to the prolonged urate-lowering effect of the drug. []
Q3: Beyond urate lowering, what other effects does Allopurinol have?
A: Studies suggest that allopurinol may have other beneficial effects beyond its urate-lowering action. These include antioxidant effects, improvement in endothelial function, and reduction in oxidative stress. These effects might contribute to potential benefits in conditions like chronic heart failure and cardiovascular disease. [, , ]
Q4: What is the molecular formula and weight of Allopurinol?
A4: The molecular formula of allopurinol is C5H4N4O, and its molecular weight is 136.11 g/mol.
Q5: Is there information available about the stability of Allopurinol under different conditions?
A5: While the provided abstracts don't delve into specific material compatibility or stability data beyond its use in biological systems, it's crucial to consult comprehensive drug formularies and research articles for detailed information on storage, handling, and potential incompatibilities with other substances.
Q6: Allopurinol is not typically described as having catalytic properties. Why?
A: Allopurinol functions as an enzyme inhibitor, meaning it binds to and blocks the activity of xanthine oxidase. It doesn't catalyze a chemical reaction itself. []
Q7: How is Allopurinol absorbed and metabolized in the body?
A: Allopurinol is well-absorbed after oral administration. It is primarily metabolized in the liver to oxypurinol, which is also an active inhibitor of xanthine oxidase. []
Q8: What factors can affect the pharmacokinetics of Allopurinol?
A: Renal function is a major determinant of allopurinol elimination. Patients with impaired renal function may require dose adjustments to avoid drug accumulation and potential toxicity. [, ]
Q9: Does the presence of other medical conditions affect Allopurinol's actions?
A: The presence of conditions like chronic kidney disease can influence both Allopurinol dosage and its potential for adverse effects. Careful monitoring of renal function is crucial in these patients. [, ]
Q10: Are there known mechanisms of resistance to Allopurinol?
A: While not extensively discussed in the provided abstracts, some individuals may not achieve adequate urate lowering with Allopurinol due to factors like poor adherence to therapy, genetic variations affecting drug metabolism, or the use of medications that interfere with Allopurinol's action. []
Q11: What is the most serious adverse reaction associated with Allopurinol?
A: Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially life-threatening adverse reaction to allopurinol. It is characterized by fever, rash, eosinophilia, liver dysfunction, and kidney failure. [, , ]
Q12: Is there a genetic test available to predict the risk of Allopurinol hypersensitivity syndrome?
A: Yes, the HLA-B*58:01 allele has been strongly associated with an increased risk of AHS, particularly in Han Chinese, Thai, and Korean populations. [, , ]
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