Absorption, Distribution and Excretion
Azaribin is well absorbed after oral administration… After absorption, azaribin is almost completely deacetylated to azauridine in the blood, with trace amounts of the monoacetyl derivative detectable. Peak plasma concentrations of azauridine are reached after 2 to 4 hours, and the half-life of the plasma clearance curve is approximately 6 to 8 hours. (6-Azauridine Triacetyl Derivative) Unlike azauracil, azauridine cannot cross the blood-brain barrier and is undetectable in cerebrospinal fluid. Significant concentrations of azauracil can be detected in cerebrospinal fluid when neurotoxicity is present. Approximately 95% of the ingested dose of azaribin is excreted in the urine as azauridine within 16 hours. In 11 patients with advanced cancer, 2',3',5'-triacetyl-6-azuridine was administered orally. Compared to free 6-azuridine, this compound is rapidly absorbed from the gastrointestinal tract. High plasma concentrations were maintained within an 8-hour interval between two doses of the acetylated derivative. The metabolism of intravenously injected orotic acid-7-C14 and the excretion of orotic acid in urine confirmed that the conversion of orotic acid to uridine nucleotides was inhibited in treated patients. The observed metabolic effects and clinical changes were comparable to those produced by intravenous administration of an equivalent dose of 6-azauridine. /2',3',5'-Triacetyl-6-azauridine/
In normal rats and adjuvant-induced polyarthritis rats, the distribution of (14)C was similar, but the concentration of (14)C in the liver of the latter was twice that of the former. Approximately 1 hour after intravenous administration, the concentration of (14)C in the fetus of pregnant rats was one-third that in the maternal circulation.

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Metabolism/Metabolites
L1210 cells incubated with /6-azauridine/ AzUrd contained a novel 254 nm uptake component that was not found in control cells. It appears to be 6-azuridine-5'-triphosphate, as it is the only peak in the triphosphate region of the chromatogram containing 3H, which was detected after incubation of cells with [3H]AzUrd. ... Azuridine is metabolized to aziridine by intestinal microbes... Azuridine is converted intracellularly to 6-azuridine acid.../6-azuridine triacetyl derivative/ After oral administration, approximately 45% of 2',3',5'-tri-O-acetyl-6-azuridine (TA-6-azuridine) is excreted in the urine of rats and humans as its deacetylated product. In rat urine, TA-6-azuridine is almost entirely excreted as free 6-azuridine, while in humans, significant amounts of mono-O-acetyl-azuridine (MA-6-azuridine) are also detected. Furthermore, approximately 35% of the dose was present as MA-6-azuridine in rat feces collected within 48 hours after administration. TA-6-azauridine and its deacetylation products were not excreted in rat bile. 6-azauridine deribosylation product 6-azauridine was not detected in the urine, feces, or bile of the rats studied. 6-azauridine triacetyl derivatives/
For more complete metabolite/metabolite data on 6-azauridine (7 metabolites in total), please visit the HSDB record page.

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Biological half-life
After absorption, azauridine is almost completely deacetylated to azauridine in the blood, with trace amounts of monoacetyl derivatives detectable. Peak plasma concentrations of azauridine are reached after 2 to 4 hours, and the half-life of the plasma clearance curve is approximately 6 to 8 hours. 6-azauridine triacetyl derivatives/

Interactions
A phase I study included 16 unselected patients with unresectable hepatocellular carcinoma who received 261 cycles of D-galactosamine and 6-azauridine prior to 5-fluorouridine treatment. 30% of patients survived for more than one year without tumor progression or change in performance status. The chemotherapy regimen was well-tolerated. The only extrahepatic side effects were leukopenia and/or thrombocytopenia, which were reversible upon dose reduction of 5-fluorouridine. Due to the heterogeneity of the 16 patients treated to date, a definitive statistical assessment of the reported clinical observations and outcomes is not yet possible. In three trials, we investigated the effect of pyridoxine on 6-azauridine triacetate (6-AzUrd-TA)-induced hyperβ-alanineemia in New Zealand white rabbits. In all three experiments, animals were administered the drug via gavage: Group 1 (control group) received drinking water; Group 2 received 6-AzUrd-TA; and Group 3 received 6-AzUrd-TA in combination with pyridoxine. β-alanine was not detected in the pretreated samples of the control group, the 6-AzUrd-TA group, and the 6-AzUrd-TA combined with pyridoxine group. However, high concentrations of β-alanine were detected on days 4 and 7 in animals treated with 6-AzUrd-TA at daily doses of 1.0 g/kg and 0.5 g/kg body weight, respectively (191.0 ± 91.6 nmol/ml, 220.2 ± 116.3 nmol/ml, and 103.2 ± 64.4 nmol/ml, respectively). In all three experiments, concomitant administration of pyridoxine at a daily dose of 50 mg/kg body weight significantly reduced drug-induced hyperβ-alanineemia (p ≤ 0.05). These results indicate that repeated daily oral administration of 6-AzUrd-Ta leads to elevated serum β-alanine levels, which can be partially inhibited by oral pyridoxine. These results also indirectly support the hypothesis that 6-AzUrd-TA-induced hyperβ-alanineemia is at least partially caused by the inhibition of β-alanine-degrading enzymes coenzymes with pyridoxal phosphate. /6-Azuridine Triacetate/
We tested the effects of 25 metabolites (purines, pyrimidines, nucleosides, and nucleosides) in synergistic inhibition of Newcastle disease virus (NDV) replication with 6-azuridine (AzUrd). Except for deoxyadenosine and cyclic adenosine monophosphate, all natural adenine derivatives exhibited ATP-like synergistic effects with AzUrd. Glutamine in combination with AzUrd did not inhibit NDV replication. The inhibitory effect of AzUrd in combination with adenine derivatives could be reversed by guanosine, uridine, and cytidine, but not by orotic acid or orotic acid nucleotides.

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Non-human toxicity values
Cat intraperitoneal LD50: 2400 mg/kg
Dog intraperitoneal LD50: 3400 mg/kg
Mouse intraperitoneal LD50: 11250 mg/kg
Rats intraperitoneal LD50: 9400 mg/kg
For more complete non-human toxicity data for 6-azauridines (of 6), please visit the HSDB records page.

[1]. Robak T, Robak P. Purine nucleoside analogs in the treatment of rarer chronic lymphoid leukemias. Curr Pharm Des. 2012;18(23):3373-88.

6-Azuridine is an N-glycosyl-1,2,4-triazine compound. It has dual effects of antitumor, antimetabolite, and drug metabolism. 6-Azuridine is a synthetic triazine analog of uridine and possesses antimetabolite activity. 6-Azuridine inhibits de novo pyrimidine synthesis and DNA synthesis, and is converted intracellularly into monophosphate, diphosphate, and triphosphate derivatives, which can be incorporated into RNA and inhibit protein synthesis. It is a triazine nucleoside used as an antitumor and antimetabolite drug. It interferes with pyrimidine biosynthesis, thereby preventing the formation of cellular nucleic acids. Its triacetate form also has anti-psoriatic activity. Mechanism of Action: 6-Azuridine (AzUrd) is a broad-spectrum antimetabolite drug that inhibits the replication of DNA and RNA viruses. Previous studies have shown that several viruses sensitive to AzUrd induce elevated uridine kinase levels, which may explain the selective activity of AzUrd against these viruses. This study compared the orotic acid metabolic pathways of AzUrd-sensitive and drug-resistant viruses by labeling cells with [14C]-orotic acid during the viral infection incubation period. No differences were detected in vaccinia virus, Newcastle disease virus, and vesicular stomatitis virus using this method. At the highest concentration of the antimetabolite, AzUrd inhibited orotic acid translocation into cells by up to 30% and orotic acid incorporation into cellular RNA by up to 50% (considering the aforementioned 30% inhibition rate). This suggests that, in addition to blocking orotic acid decarboxylase, AzUrd may also act on other sites inhibiting viral proliferation. ...Pyrazofurano and 6-azouridine are two nucleoside analogues that are thought to interfere with OMP decarboxylase (another enzyme involved in the biosynthesis of pyrimidine ribonucleotides), thereby enhancing the cytotoxic activity of Ce-Cyd. Azacytidine readily deaminates to form azauridine and is further degraded. It can be incorporated into DNA and alter gene expression. ...azuridine induces DNA hypomethylation both in vivo and in vitro.

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Therapeutic Uses
A triazine nucleoside used as an antitumor antimetabolite. It interferes with pyrimidine biosynthesis, thereby preventing the formation of cellular nucleic acids. The triacetate form of 6-azuridine also has anti-psoriatic activity.
Antimetabolite for the treatment of psoriasis and mycosis fungoides/6-azuridine triacetate/
/Previous Uses/Azuridine and its triacetyl derivative azaribine have been shown to be valuable in the treatment of psoriasis.
/Previous Uses/Combined use of 6-azuridine, 6-mercaptopurine, and vincristine can effectively induce remission in children with acute myeloid leukemia.
For more complete data on the therapeutic uses of 6-azuridine (17 in total), please visit the HSDB record page.

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Drug Warning
The antimetabolite 6-azouridine can block the de novo synthesis of pyrimidines and lead to elevated serum levels of multiple amino acids, including homocysteine. Due to arterial and venous thromboembolic events in some psoriasis patients, 6-azouridine has been discontinued for clinical treatment of psoriasis. This study, using standard animal models of venous and arterial thrombosis, confirmed that oral or intravenous administration of 6-azouridine can induce thrombosis without causing hyperhomocysteinemia.
While this drug may have significant benefits in treating acute flare-ups of psoriatic arthritis, it can cause unexplained exacerbations in patients with rheumatoid arthritis. /6-azouridine triacetyl derivative/
Preparations must be of high quality because even small amounts of unacetylated azouridine can be metabolized by gut microbes into the neurotoxic metabolite azouridine. /6-Azauridine Triacetyl Derivatives/
High-dose azaribin (200 mg/kg daily) can effectively induce temporary remission in patients with severe psoriasis, but may cause serious neurotoxicity…/6-Azauridine Triacetate/
Administration of 6-Azauridine triacetate (6-AzUrd-TA) can cause changes in amino acid metabolism in experimental animals and humans. This effect is dose-related. The amino acid changes induced by 6-AzUrd-TA are similar to those in congenital homocystinuria, β-alanine hyperacidity, and hyperhistinosinemia. Inhibition of certain enzymes with pyridoxal phosphate as a coenzyme appears to be a common feature of these changes. There is evidence of a link between 6-AzUrd-TA-induced homocysteine hyperacidity and thrombotic events…/6-Azauridine Triacetate/

C8H11N3O6

245.19

245.064

54-25-1

5901

White to off-white solid powder

2.1±0.1 g/cm3

157-159 °C(lit.)

1.795

-1.96

4

7

2

17

372

4

C1=NN(C(=O)NC1=O)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O

WYXSYVWAUAUWLD-SHUUEZRQSA-N

InChI=1S/C8H11N3O6/c12-2-3-5(14)6(15)7(17-3)11-8(16)10-4(13)1-9-11/h1,3,5-7,12,14-15H,2H2,(H,10,13,16)/t3-,5-,6-,7-/m1/s1

2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazine-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 : 25 mg/mL (101.96 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.20 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 (10.20 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 25.0 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 3: ≥ 2.5 mg/mL (10.20 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.)