Cedazuridine (compound 7a) exhibits superior acid stability [1]. Cedazuridine (0-10 μM; 72 h) does not amplify AZA (5-Azacytidine)'s growth-inhibitory action on AML cell lines [2].

In mouse MOLM-13 CDX and PDX models, Chidazuridine (3 mg/kg; oral; once daily for 7 days) plus 2.5 mg/kg AZA led to tumor remission [2].

Animal/Disease Models: Female NSGS mice, 6-8 weeks old, human cell line-derived (CDX) and primary patient-derived xenograft (PDX) models [2]
Doses: 3 mg/kg
Route of Administration: Orally, with 2.5 mg combination/kg AZA one time/day for 7 days
Experimental Results: Combination with AZA reduces leukemic expansion in cell line-derived xenografts and demonstrates preliminary safety and efficacy in PDX model of primary AML sex.

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Animal/Disease Models: NSGS male mice [2]
Doses: 1, 3, 10 and 30 mg/kg
Route of Administration: po (po (oral gavage)) combined with 2.5 mg/kg AZA (pharmacokinetic/PK/PK study)
Experimental Results: The AUC of oral AZA was There was a dose-dependent increase and in comparison with standard ip AZA doses.

Absorption, Distribution and Excretion
After once-daily oral administration of cedazarone (100 mg) and decitabine (35 mg) for five consecutive days, the results showed that the AUC and steady-state AUC (coefficient of variation) of decitabine on day 1 were 103 (55%) and 178 (53%) nghr/mL, respectively, while those of cedazarone were 2950 (49%) and 3291 (45%) nghr/mL, respectively. Overall, the cumulative AUC of decitabine over 5 days was 851 (50%). Similarly, the Cmax of decitabine and cedazarone were 145 (55%) and 371 (52%) ng/mL, respectively. The median time to peak concentration (Tmax) of decitabine was 1 hour (range 0.3 to 3.0 hours), and that of cedazarone was 3 hours (range 1.5 to 6.1 hours). The bioavailability of decitabine was assessed by comparing the AUC values of oral decitabine combined with cidazaloride with intravenous decitabine alone. Results showed that on day 1, the bioavailability was 60% (90% CI: 55–65%). On day 5, and considering the cumulative dose over day 5, the corresponding values were 106% (90% CI: 98–114) and 99% (90% CI: 93–106), respectively. Therefore, the oral bioavailability of decitabine was close to 100% over a 5-day treatment period. Approximately 46% of cidazaloride was excreted in the urine, of which 21% was unchanged; 51% was excreted in the feces, of which 27% was unchanged. The apparent volumes of distribution (and their coefficients of variation) of decitabine and cidazaloride at steady state were 417 (54%) and 296 (51%), respectively. The apparent steady-state clearance of cidazaloride was 30.3 L/h with a coefficient of variation of 46%.

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Metabolism/Metabolites
The metabolism of chidazoridine is not fully understood. It is known that chidazoridine is converted to an epimer, which inhibits cytidine deaminase at approximately a 10-fold reduced rate, and subsequently degrades via an unknown pathway.Biological Half-Life
The steady-state half-life of chidazoridine is 6.7 hours, with a coefficient of variation of 19%.
The steady-state half-life of chidazoridine is 6.7 hours, with a coefficient of variation of 19%.

Hepatotoxicity
In pre-registration trials of decitabine in combination with cidazaloride, 20% to 37% of patients experienced elevated serum transaminases, but these were transient and usually mild. 1% to 3% of patients experienced ALT elevations exceeding 5 times the upper limit of normal, which usually resolved rapidly with dose adjustment or discontinuation of the drug. However, some patients experienced elevated ALT accompanied by elevated serum bilirubin, but all cases were caused by other factors such as sepsis, pancreatitis, and myocarditis. Since its approval, its clinical use has become increasingly widespread, and there are currently no published reports of clinically significant liver injury caused by the combined use of cidazaloride and decitabine. Probability score: E (Suspected but unconfirmed rare cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Cidazaloride is used in combination with decitabine in a combination formulation. Most data suggest that mothers receiving anti-tumor drug treatment should avoid breastfeeding. Breastfeeding may be safe during intermittent treatment with cidazaloride-decitabine if there is an appropriate period of lactation. The manufacturer recommends discontinuing breastfeeding for two weeks after the last dose of the cidazaloride-decitabine combination. Chemotherapy may adversely affect the normal microbiota and chemical composition of breast milk. Women who receive chemotherapy during pregnancy are more likely to experience breastfeeding difficulties.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
A telephone follow-up study surveyed 74 women who received cancer chemotherapy at the same center during the second or third trimester to determine their postpartum breastfeeding success. Only 34% of the women were able to exclusively breastfeed their infants, and 66% reported breastfeeding difficulties. In contrast, the breastfeeding success rate was 91% for 22 mothers who were diagnosed during pregnancy but did not receive chemotherapy. Other statistically significant correlations included: 1) Mothers experiencing breastfeeding difficulties received an average of 5.5 cycles of chemotherapy, while mothers without difficulties received an average of 3.8 cycles; 2) Mothers with breastfeeding difficulties received their first chemotherapy cycle an average of 3.4 weeks earlier. Of the nine women receiving the fluorouracil-containing regimen, eight experienced breastfeeding difficulties. Protein Binding: Neither decitabine nor chidazolidine showed extensive plasma protein binding. Decitabine showed binding rates of 4% to 6% in the dose range of 17 to 342 ng/mL, while chidazolidine showed binding rates of 34% to 38% in the dose range of 1000 ng/mL to 50000 ng/mL.

[1]. Ferraris D, et al. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27; 57(6):2582-8.
[2]. Ramsey H E, et al. Oral azacitidine and cedazuridine approximate parenteral azacitidine efficacy in murine model. Targeted Oncology, 2020, 15(2): 231-240.

Myelodysplastic syndromes (MDS) are a group of hematopoietic malignancies that cause varying degrees of cytopenia and progress to secondary acute myeloid leukemia (sAML), which is almost always fatal if left untreated. Hypomethylating agents such as decitabine and azacitidine treat MDS by inducing DNA hypomethylation and apoptosis in cancer cells. Although these compounds are effective, they are rapidly metabolized by cytidine deaminase (CDA) before entering systemic circulation after oral administration, thus requiring intramuscular or intravenous injection. Cidazoridine, a fluorinated tetrahydrouridine derivative, is specifically designed to inhibit CDA, thereby facilitating oral administration of hypomethylating agents. Cedazoridine was first reported in 2014 and received FDA approval on July 7, 2020, for use in combination with decitabine, marketed by Astex Pharmaceuticals Inc. under the brand name INQOVI®.
Cedazoridine is a small molecule inhibitor of cytidine deaminase, used as a pharmacodynamic enhancer of decitabine to improve the oral bioavailability of this DNA methyltransferase inhibitor in the treatment of myelodysplastic syndromes. The incidence of mild elevations in serum enzymes during oral decitabine combined with cedazoridine is low, usually attributed to decitabine. No clinically significant cases of liver injury have been found to be associated with this oral combination therapy.
Cedazoridine is an oral synthetic nucleoside analog derived from tetrahydrouridine (THU) and cytidine deaminase inhibitors (CDAi), possessing the potential to inhibit cytidine degradation. After oral administration, cedazoridine binds to and inhibits the activity of cytidine deaminase (CDA). CDA is primarily found in the gastrointestinal tract and liver, catalyzing the deamination of cytidine and its analogues. When used in combination with cytidine drugs (such as the antitumor hypomethylating drug decitabine), cedazoridine specifically prevents cytidine degradation, thereby improving its bioavailability and efficacy. Furthermore, this allows for a reduction in the dosage of decitabine, thereby reducing decitabine-related gastrointestinal toxicity. Drug Indications Cidazaredin, in combination with decitabine, is used to treat myelodysplastic syndromes (MDS), including MDS with refractory anemia, MDS with refractory anemia and ringed sideroblasts, MDS with refractory anemia and blastosis, MDS with an International Prognostic Score (IPSS) of intermediate-1, intermediate-2, or high risk, and chronic myelomonocytic leukemia (CMML). Mechanism of Action Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic malignancies caused by various underlying mutations, characterized by peripheral blood cytopenia, and may eventually progress to secondary acute myeloid leukemia (sAML). More than 45 mutated genes are commonly found in patients with myelodysplastic syndromes (MDS), including genes involved in DNA methylation and repair, histone modification, RNA splicing, transcription, signal transduction, and cell adhesion. It is hypothesized that initial clonal originator mutations lead to the gradual accumulation of secondary mutations, promoting disease progression to secondary acute myeloid leukemia (sAML). Demethylating agents, such as decitabine, are metabolized into triphosphate derivatives, which are then incorporated into DNA. Once incorporated, these drugs inhibit the activity of DNA methyltransferases (such as DNMT1), leading to progressive hypomethylation of DNA, ultimately activating tumor suppressor genes and apoptosis pathways. However, orally administered demethylating agents are readily metabolized by cytidine deaminases and therefore usually require intramuscular or intravenous administration. Combination therapy with the highly potent cytidine deaminase inhibitor cedazuridine can significantly improve the oral bioavailability of decitabine, thus enabling combined oral therapy.

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Pharmacodynamics
Cidazari is a cytidine deaminase inhibitor, often used in combination with hypomethylating drugs such as decitabine to improve its oral bioavailability. Combination therapy of cidazari with hypomethylating drugs may cause bone marrow suppression and embryo-fetal toxicity; therefore, administration should be under appropriate monitoring.

C9H14F2N2O5

268.214669704437

268.087

1141397-80-9

Cedazuridine hydrochloride

25267009

White to off-white solid powder

162-165

-1.1

4

7

2

18

343

4

C1CN(C(=O)N[C@@H]1O)[C@H]2C([C@@H]([C@H](O2)CO)O)(F)F

VUDZSIYXZUYWSC-DBRKOABJSA-N

InChI=1S/C9H14F2N2O5/c10-9(11)6(16)4(3-14)18-7(9)13-2-1-5(15)12-8(13)17/h4-7,14-16H,1-3H2,(H,12,17)/t4-,5-,6-,7-/m1/s1

(R)-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-hydroxytetrahydropyrimidin-2(1H)-one

WHO 10741 E7727 WHO-10741 E-7727WHO10741 E 7727

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ~50 mg/mL (~186.42 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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