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 orally administered dose is absorbed from the gastrointestinal tract.
The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U.
Less than 20% of a dose of conventional cytarabine is absorbed from the GI tract, and the drug is not effective when administered orally. Following subcutaneously or im injection of conventional cytarabine H 3, peak plasma concentrations of radioactivity occur within 20-60 min and are considerably lower than those attained after iv administration. Continuous iv infusions of conventional cytarabine produce relatively constant plasma concn of the drug in 8-24 hr.
Cytarabine is rapidly and widely distributed into tissues and fluids, including liver, plasma, and peripheral granulocytes. Following rapid IV injection of cytarabine in one study, approximately 13% of the drug was bound to plasma proteins.
Cytarabine crosses the blood-brain barrier to a limited extent. During a continuous IV or subcutaneous infusion, cytarabine concentrations in the CSF are higher than those attained after rapid IV injection and are about 40-60% of plasma concentrations. Most of an intrathecal dose of cytarabine diffuses into the systemic circulation but is rapidly metabolized and usually only low plasma concentrations of unchanged drug occur.
The drug apparently crosses the placenta. It is not known if cytarabine or ara-U is distributed into milk.
For more Absorption, Distribution and Excretion (Complete) data for CYTARABINE (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic.
Cytarabine is rapidly and extensively metabolized mainly in the liver but also in kidneys, GI mucosa, granulocytes, and to a lesser extent in other tissues by the enzyme cytidine deaminase, producing the inactive metabolite 1-ß-d-arabinofuranosyluracil (ara-U, uracil arabinoside). After the initial distribution phase, more than 80% of the drug in plasma is present as ara-U. In the CSF, only minimal amounts of cytarabine are converted to ara-U because of low CSF concentrations of cytidine deaminase. Intracellularly, cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to cytarabine triphosphate, the active metabolite of the drug. Cytarabine triphosphate is inactivated by a pyrimidine nucleoside deaminase, which produces the uracil derivative.
The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U (1-(beta)-D-arabinofuranosyluracil or uracilarabinoside), followed by urinary excretion of ara-U. In contrast to systemically administered cytarabine, which is rapidly metabolized to ara-U, conversion to ara-U in the CSF is negligible after intrathecal administration because of the significantly lower cytidine deaminase activity in the CNS tissues and CSF. The CSF clearance rate of cytarabine is similar to the CSF bulk flow rate of 0.24 mL/min. /Cytarabine liposome injection/
Cytarabine must be converted to the 5'-monophosphate nucleotide by deoxycytidine kinase to be active. Ara-cytidine diphosphate &/or ara-cytidine triphosphate are presumably the form that inhibit DNA polymerase & block ribonucleoside diphosphate reductase.
Hepatic.

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Biological Half-Life
10 minutes
After rapid IV injection of cytarabine, plasma drug concentrations appear to decline in a biphasic manner with a half-life of about 10 minutes in the initial phase and about 1-3 hours in the terminal phase. Cytarabine reportedly undergoes triphasic elimination in some patients. After intrathecal injection, cytarabine concentrations in the CSF reportedly decline with a half-life of about 2 hours.
Peak levels were followed by a biphasic elimination profile with a terminal phase half-life of 100 to 263 hours over a dose range of 12.5 mg to 75 mg. In contrast, intrathecal administration of 30 mg of free cytarabine showed a biphasic CSF concentration profile with a terminal phase half-life of 3.4 hours. /Cytarabine liposome injection/
After iv admin, there is a rapid phase of disappearance of AraC (half-life = 10 min), followed by a slower phase of elimination with a half-time of about 2.5 hr ... After intrathecal admin of the drug at a dose of 50 mg/sq m ... peak concn of 1 to 2 mM are achieved, which decline slowly with a terminal half-life of approx 3.4 hr.

Hepatotoxicity
Serum aminotransferase elevations occur in 5% to 10% of patients on conventional doses of cytarabine and a greater proportion (9% to 75%) at higher doses. However, the serum enzyme elevations are rarely associated with symptoms and are generally self-limited and resolve rapidly, rarely requiring dose modification. Cases of clinically apparent liver injury attributed to cytarabine have been reported but are uncommon. The time to onset was usually within the first few cycles of therapy, and the pattern of serum enzyme elevations ranged from cholestatic to hepatocellular. Immunoallergic and autoimmune features were generally not present. Antineoplastic regimens, including cytarabine, have been implicated in cases of sinusoidal obstruction syndrome and peliosis, but the role of cytarabine in these reactions was unclear. Many examples of liver injury attributed to cytarabine in the literature were typical of jaundice of sepsis rather than acute hepatocellular or cholestatic injury, although high doses of cytarabine may cause hyperbilirubinemia independent of hepatic injury.
Likelihood score: C (probable cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the excretion of cytarabine into breastmilk. However, the drug has a short half-life of 2 to 3 hours after intravenous administration, so it should be eliminated from milk a day after intravenous administration. Very little information is available on the use of cytarabine during breastfeeding. In one case, a mother began breastfeeding her infant 3 weeks after receiving cytarabine, mitoxantrone and etoposide intravenously, with no apparent harm to her infant. After intrathecal administration of the liposomal formulation of cytarabine, drugs levels in plasma are barely detectable, and are unlikely to appear in milk in clinically relevant amounts.
◉ Effects in Breastfed Infants
One mother received 3 daily doses of 6 mg/sq. m. of mitoxantrone intravenously along with 5 daily doses of etoposide 80 mg/sq. m. and cytarabine 170 mg/sq. m. intravenously. She resumed breastfeeding her infant 3 weeks after the third dose of mitoxantrone at a time when mitoxantrone was still detectable in milk. The infant had no apparent abnormalities at 16 months of age. However, after 3 weeks of abstinence from breastfeeding, it is unlikely that cytarabine was present in milk during breastfeeding.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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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 can cause developmental toxicity according to an independent committee of scientific and health experts.
Cytarabine appears as colorless crystals. Used as an antiviral agent.
Crystals (from aqueous ethanol) or fluffy white powder. (NTP, 1992)
Cytarabine is a pyrimidine nucleoside in which cytosine is attached to D-arabinofuranose via a beta-N(1)-glycosidic bond. Used mainly in the treatment of leukaemia, especially acute non-lymphoblastic leukaemia, cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. It also has antiviral and immunosuppressant properties. It has a role as an antineoplastic agent, an antimetabolite, an antiviral agent and an immunosuppressive agent. It is a beta-D-arabinoside, a pyrimidine nucleoside and a monosaccharide derivative. It is functionally related to a cytosine.
A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)
Cytarabine is a Nucleoside Metabolic Inhibitor. The mechanism of action of cytarabine is as a Nucleic Acid Synthesis Inhibitor.
Cytarabine is a cytosine analogue and antineoplastic agent used largely in the therapy of acute leukemia. Cytarabine is associated with a low rate of transient serum enzyme and bilirubin elevations during therapy, but has only rarely been implicated in cases of clinically apparent acute liver injury with jaundice.
Cytarabine is an antimetabolite analogue of cytidine with a modified sugar moiety (arabinose instead of ribose). Cytarabine is converted to the triphosphate form within the cell and then competes with cytidine for incorporation into DNA. Because the arabinose sugar sterically hinders the rotation of the molecule within DNA, DNA replication ceases, specifically during the S phase of the cell cycle. This agent also inhibits DNA polymerase, resulting in a decrease in DNA replication and repair. (NCI04)
A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)
A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)
See also: Cytarabine; daunorubicin (component of).

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Drug Indication
For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia. Cytarabine is indicated in combination with [daunorubicin] for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.
FDA Label
Intrathecal treatment of lymphomatous meningitis. In the majority of patients such treatment will be part of symptomatic palliation of the disease.

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Mechanism of Action
Cytarabine acts through direct DNA damage and incorporation into DNA. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported.
Cytarabine is converted intracellularly to the nucleotide, cytarabine triphosphate (ara-CTP, cytosine arabinoside triphosphate). Although the exact mechanism(s) of action of cytarabine has not been fully elucidated, cytarabine triphosphate appears to inhibit DNA polymerase by competing with the physiologic substrate, deoxycytidine triphosphate, resulting in the inhibition of DNA synthesis. Although limited, incorporation of cytarabine triphosphate into DNA and RNA may also contribute to the cytotoxic effects of the drug.
Cytarabine is a potent immunosuppressant which can suppress humoral and/or cellular immune responses; however, the drug does not decrease preexisting antibody titers and has no effect on established delayed hypersensitivity reactions.
Cytarabine liposome injection is a sustained-release formulation of the active ingredient cytarabine designed for direct administration into the cerebrospinal fluid (CSF). Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5'-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA polymerase. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. /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.)