DNA synthesis ( IC50 = 16 nM )

Cytarabine undergoes phosphorylation into a triphosphate form (Ara-CTP) through the action of deoxycytidine kinase (dCK), which inhibits the function of DNA and RNA polymerases and competes with dCTP for incorporation into DNA. With an IC50 of 16 nM, cytarabine exhibits greater growth inhibitory activity against wild-type CCRF-CEM cells than it does against other acute myelogenous leukemia (AML) cells[1]. It appears that cytarabine causes apoptosis in rat sympathetic neurons at 10 μM; the highest toxicity is at 100 μM, which kills over 80% of the neurons in 84 hours through the activation of caspase-3 and the release of mitochondrial cytochrome-c. The toxicity can be delayed by bax deletion and attenuated by p53 knockdown[2].

Cytarabine (250 mg/kg) also results in placental growth retardation and increases the apoptosis of placental trophoblastic cells in the placental labyrinth zone of pregnant Slc:Wistar rats. This process begins three hours after the treatment, peaks at six hours, and returns to control levels at forty-eight hours. Notably, p53 protein and p53 transcriptional target genes, including p21, cyclin G1, fas, and caspase-3 activity, are significantly increased[3]. The use of higher dosages of Cytarabine does not appear to contribute to its antileukaemic effectiveness in humans. Cytarabine is highly effective against acute leukaemias, which cause the chCytarabineteristic G1/S blockage and synchronization, and increases the survival time for leukaemic Brown Norway rats in a weak dose-related fashion[4].

Intraperitoneal (i.p.) injection of 250 mg/kg Cytarabine is administered to pregnant rats on Day 13 of gestation (GD13). Congenital defects and growth retardation are frequently found in perinatal fetuses under the circumstances of this experiment, but the incidence of fetal death is not noticeably elevated. Following treatment, six dams are killed by heart puncture under ether anesthesia at 1, 3, 6, 9, 12, 24, and 48 hours. The placentas are then collected. In GD13, six pregnant rats serve as controls. They receive an intraperitoneal injection of the same volume of PBS and are killed concurrently with the groups treated with cytarabine. Three of the six dams collected at each time point are utilized for histopathological examinations, and the remaining three are used for RT-PCR (reverse transcription-polymerase chain reaction) analysis.

Absorption, Distribution and Excretion
Less than 20% of the oral dose is absorbed from the gastrointestinal tract. The primary elimination pathway of cytarabine is metabolism to the inactive compound cytarabine (ara-U), followed by urinary excretion. Less than 20% of conventional cytarabine is absorbed from the gastrointestinal tract, rendering it ineffective orally. Following subcutaneous or intramuscular injection of conventional cytarabine H3, peak plasma radioactivity is reached within 20-60 minutes and is significantly lower than the peak concentration after intravenous administration. Continuous intravenous infusion of conventional cytarabine maintains relatively stable plasma drug concentrations for 8-24 hours. Cytarabine rapidly and extensively distributes to tissues and body fluids, including the liver, plasma, and peripheral blood granulocytes. In one study, approximately 13% of the drug bound to plasma proteins after rapid intravenous injection of cytarabine. Cytarabine crosses the blood-brain barrier to a limited extent. With continuous intravenous or subcutaneous infusion, the concentration of cytarabine in cerebrospinal fluid is higher than that after rapid intravenous injection, approximately 40-60% of the plasma concentration. Most of the intrathecal cytarabine diffuses into the systemic circulation but is rapidly metabolized, with only low concentrations of the unchanged drug typically entering the plasma. The drug appears to cross the placenta. It is currently unclear whether cytarabine or ara-U is excreted into breast milk. For more complete data on the absorption, distribution, and excretion of cytarabine (7 types), please visit the HSDB record page. Metabolism/Metabolites Hepatic Metabolism. Cytarabine is primarily and rapidly metabolized in the liver, but also in the kidneys, gastrointestinal mucosa, granulocytes, and in small amounts in other tissues. During metabolism, cytidine deaminase converts cytarabine into the inactive metabolite 1-β-D-arabinofuranosyluracil (ara-U). After the initial distribution phase, over 80% of the drug remains in the plasma as ara-U. Due to the low concentration of cytidine deaminase in cerebrospinal fluid (CSF), only a very small amount of cytarabine is converted to ara-U in CSF. Intracellularly, cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to cytarabine triphosphate (CTP), the active metabolite of the drug. CTP is inactivated by pyrimidine nucleoside deaminase to generate uracil derivatives. The main clearance pathway of cytarabine is metabolism to the inactive compound ara-U (1-(β)-D-arabinofuranosyluracil or uracil-arabinoside), which is subsequently excreted in the urine. Unlike cytarabine, which is rapidly metabolized to ara-U after systemic administration, after intrathecal administration, the amount of cytarabine converted to ara-U in CSF is negligible due to the significantly reduced activity of cytidine deaminase in central nervous system tissues and CSF. The CSF clearance rate of cytarabine is similar to the overall CSF flow rate of 0.24 mL/min. /Cytarabine Liposome Injection/
Cytarabine must be converted to 5'-monophosphate nucleotides by deoxycytidine kinase to exert its activity. It is speculated that cytarabine diphosphate and/or cytarabine triphosphate, which inhibit DNA polymerase and block ribonucleoside diphosphate reductase, are its main forms.
Hepatic metabolism.
Biological half-life
10 minutes
Following rapid intravenous injection of cytarabine, plasma drug concentrations exhibit a biphasic decline, with an initial half-life of approximately 10 minutes and a terminal half-life of approximately 1-3 hours. Cytarabine has been reported to exhibit triphasic elimination in some patients. Following intrathecal injection, cytarabine concentrations in cerebrospinal fluid have been reported to decrease, with a half-life of approximately 2 hours.
In the dose range of 12.5 mg to 75 mg, after peak concentration, a biphasic elimination curve is observed, with a terminal half-life of 100 to 263 hours. In contrast, intrathecal injection of 30 mg of free cytarabine also showed a biphasic cerebrospinal fluid concentration profile with a terminal half-life of 3.4 hours. /Cytarabine liposome injection/
After intravenous injection, cytarabine undergoes a rapid disappearance phase (half-life = 10 minutes), followed by a slower elimination phase with a half-life of approximately 2.5 hours…After intrathecal injection of a dose of 50 mg/m²…a peak concentration of 1 to 2 mM is reached, followed by a slow decline with a terminal half-life of approximately 3.4 hours.

Hepatotoxicity
Elevated serum transaminases occur in 5% to 10% of patients receiving standard doses of cytarabine, and this proportion is even higher (9% to 75%) in patients receiving higher doses. However, these serum enzyme elevations are rarely symptomatic, are usually self-limiting, and resolve rapidly, rarely requiring dose adjustments. Although there are reports of clinically significant liver injury caused by cytarabine, this is uncommon. Liver injury typically occurs within the first few cycles of treatment, with serum enzyme elevations ranging from cholestatic to hepatocellular. Immune hypersensitivity and autoimmune features are usually absent. Antitumor treatment regimens, including cytarabine, have been associated with cases of hepatic sinusoidal obstruction syndrome and hepatic purpura, but the role of cytarabine in these responses remains unclear. Many cases of liver injury attributed to cytarabine in the literature present as septic jaundice rather than acute hepatocellular or cholestatic injury, although high doses of cytarabine may cause hyperbilirubinemia unrelated to liver injury.
Probability Score: C (Possibly a cause of clinically significant liver damage).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on cytarabine being excreted into breast milk. However, the drug has a short half-life after intravenous administration, only 2 to 3 hours, so it should be cleared from breast milk within one day after intravenous administration. Information on the use of cytarabine during lactation is very limited. In one case, a mother began breastfeeding 3 weeks after receiving intravenous injections of cytarabine, mitoxantrone, and etoposide, and the infant did not experience any significant adverse reactions. After intrathecal injection of liposomal cytarabine, the drug concentration in plasma is almost undetectable, and it is unlikely to reach clinically significant concentrations in breast milk.
◉ Effects on breastfed infants
One mother received 3 intravenous injections of mitoxantrone (6 mg/m²) and 5 intravenous injections of etoposide (80 mg/m²) and cytarabine (170 mg/m²). Three weeks after the third injection of mitoxantrone, she resumed breastfeeding, at which time mitoxantrone was still detectable in the breast milk. The infant showed no obvious abnormalities at 16 months of age. However, cytarabine is unlikely to be present in breast milk three weeks after cessation of breastfeeding.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
13%

[1]. Tobias, S.C. and R.F. Borch, Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug. Mol Pharm, 2004. 1(2): p. 112-6.

[2]. Pharmacodynamics of cytarabine induced leucopenia: a retrospective cohort study. Br J Clin Pharmacol. 2015 Apr;79(4):685-91.

[3]. Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons. Cell Death Differ, 2003. 10(9): p. 1045-58.

[4]. Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta. Biol Reprod, 2004. 70(6): p. 1762-7.

[5]. Comparison of the antileukaemic activity of 5 aza-2-deoxycytidine and arabinofuranosyl-cytosine in rats with myelocytic leukaemia. Br J Cancer, 1988. 58(6): p. 730-3.

[6]. Renis HE. Antiviral activity of cytarabine in herpesvirus-infected rats. Antimicrob Agents Chemother. 1973 Oct;4(4):439-44.

Cytarabine to an independent committee of scientific and health experts, cytarabine may cause developmental toxicity. Cytarabine is a colorless crystalline solid used as an antiviral drug. It is a crystal (soluble in aqueous ethanol solution) or a fluffy white powder. (NTP, 1992) Cytarabine is a pyrimidine nucleoside in which cytosine is linked to D-arabinofuranose via a β-N(1)-glycosidic bond. Cytarabine is primarily used to treat leukemia, particularly acute non-lymphocytic leukemia. It is an antimetabolite and antitumor drug that inhibits DNA synthesis. It also has antiviral and immunosuppressive effects. It combines the functions of an antitumor drug, antimetabolite, antiviral drug, and immunosuppressant. It is a β-D-arabinoside, a pyrimidine nucleoside, and also a monosaccharide derivative. Its function is related to cytosine. Cytarabine is a pyrimidine nucleoside analog primarily used to treat leukemia, particularly acute non-lymphocytic leukemia. Cytarabine is an antimetabolite and antitumor drug that inhibits DNA synthesis. Its action is specifically targeted at the S phase of the cell cycle. It also has antiviral and immunosuppressive properties. (Excerpt from Martindale Pharmacopoeia, 30th edition, p. 472)
Cytarabine is a nucleoside metabolism inhibitor. The mechanism of action of cytarabine is as a nucleic acid synthesis inhibitor.
Cytarabine is a cytosine analog and also an antitumor drug, widely used to treat acute leukemia. The incidence of transient elevations in serum enzymes and bilirubin during cytarabine treatment is low, but it is rarely associated with clinically significant acute liver injury with jaundice.
Cytarabine is an antimetabolite analog of cytidine, with its glycosyl moiety modified (arabinose replaces ribose). Cytarabine is converted to its triphosphate form intracellularly, which then competes with cytidine for incorporation into DNA. DNA replication is halted, especially during the S phase of the cell cycle, due to the steric hindrance of arabinose hindering the rotation of the molecule within the DNA. The drug also inhibits DNA polymerase, leading to reduced DNA replication and repair. (NCI04)
Cytarabine is a pyrimidine nucleoside analog primarily used to treat leukemia, particularly acute non-lymphocytic leukemia. Cytarabine is an antimetabolite and antitumor drug that inhibits DNA synthesis. Its action is specific to the S phase of the cell cycle. It also has antiviral and immunosuppressive properties. (Excerpt from Martindale Pharmacopoeia, 30th edition, p. 472)
A pyrimidine nucleoside analog primarily used to treat leukemia, particularly acute non-lymphocytic leukemia. Cytarabine is an antimetabolite and antitumor drug that inhibits DNA synthesis. Its action is specific to the S phase of the cell cycle. It also has antiviral and immunosuppressive properties. (Excerpt from Martindale Pharmacopoeia, 30th edition, p. 472)
See also: Cytarabine; Daunorubicin (component).

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Drug Indications
Used to treat acute non-lymphocytic leukemia, acute lymphoblastic leukemia, and the blast crisis of chronic myeloid leukemia. Cytarabine, in combination with daunorubicin, is used to treat newly diagnosed treatment-related acute myeloid leukemia (t-AML) or acute myeloid leukemia with myelodysplastic associated changes (AML-MRC) in adults and children aged 1 year and older.
FDA label: Intrathecal treatment of lymphomatous meningitis. In most patients, this treatment is part of disease symptom remission.

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Mechanism of Action
Cytarabine exerts its effects through direct DNA damage and DNA incorporation. Cytarabine is cytotoxic to a variety of proliferative mammalian cells in vitro. It is cell cycle specific, primarily killing cells in the DNA synthesis phase (S phase) and, under certain conditions, blocking the cell progression from G1 phase to S phase. Although its mechanism of action is not fully elucidated, cytarabine appears to act by inhibiting DNA polymerase. There are also reports of cytarabine being incorporated into DNA and RNA in small but significant amounts.
Cytarabine is converted intracellularly to the nucleotide cytarabine triphosphate (ara-CTP, cytosine arabinoside triphosphate). Although the exact mechanism of action of cytarabine is not fully elucidated, cytarabine triphosphate (ara-CTP) appears to inhibit DNA synthesis by competing with the physiological substrate deoxycytidine triphosphate (dCTP) to inhibit DNA polymerase. While limited, the incorporation of cytarabine triphosphate into DNA and RNA may also contribute to the drug's cytotoxic effects. Cytarabine is a potent immunosuppressant that inhibits humoral and/or cellular immune responses; however, it does not reduce existing antibody titers and has no effect on established delayed-type hypersensitivity reactions. Cytarabine liposome injection is a sustained-release formulation of the active ingredient cytarabine designed for direct injection into cerebrospinal fluid (CSF). Cytarabine is a cell cycle-specific antitumor drug that acts only during the S phase of cell division. Intracellularly, cytarabine is converted to its active metabolite, cytarabine-5'-triphosphate (ara-CTP). Its mechanism of action is not fully elucidated, but ara-CTP appears to act primarily by inhibiting DNA polymerase. The incorporation of cytarabine into DNA and RNA may also be a contributing factor to its cytotoxicity. Cytarabine exhibits cytotoxicity against various proliferating mammalian cells cultured in vitro. /Cytarabine liposome injection/

C9H14CLN3O5

279.6776

279.062

C, 38.65; H, 5.05; Cl, 12.68; N, 15.02; O, 28.60

69-74-9

147-94-4 (free); 69-74-9 (HCl)

6253

White solid powder

545.7ºC at 760 mmHg

197-198 °C(lit.)

283.8ºC

4

5

2

17

383

4

Cl[H].O1[C@]([H])(C([H])([H])O[H])[C@]([H])([C@@]([H])([C@@]1([H])N1C(N=C(C([H])=C1[H])N([H])[H])=O)O[H])O[H]

KCURWTAZOZXKSJ-JBMRGDGGSA-N

InChI=1S/C9H13N3O5.ClH/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8;/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16);1H/t4-,6-,7+,8-;/m1./s1

4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one;hydrochloride

MK 8242; MK8242; MK-8242; SCH-900242; SCH 900242; SCH900242; aracytidine; cytarabine hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: 50~55 mg/mL (178.8~196.7 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.94 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 (8.94 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 (8.94 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.)