Cytarabine   中文名称: 阿糖胞苷

Microbial Metabolite; HSV-1

体外活性：阿糖胞苷（AraC）在脱氧胞苷激酶（dCK）的作用下被磷酸化成三磷酸形式（Ara-CTP），与dCTP竞争掺入DNA，然后通过抑制DNA和RNA聚合酶的功能来阻断DNA合成。与其他急性髓性白血病 (AML) 细胞相比，阿糖胞苷对野生型 CCRF-CEM 细胞表现出更高的生长抑制活性，IC50 为 16 NM。增加阿糖胞苷浓度（IC50 为 0.69 μM）会导致敏感大鼠白血病细胞系 RO/1 的代谢活性降低，并且通过转染人 wt dCK（IC50 为 0.037 μM）可大大增强细胞毒性，但转染无活性的 dCK 则不会增强细胞毒性。选择性剪接的 dCK 形式。激酶测定：在无水乙醇中制备阿糖胞苷储备溶液，并制备阿糖胞苷的系列稀释液。 CCRF-CEM 细胞悬浮在补充有 10% FBS、0.1% 庆大霉素和 1% 丙酮酸钠的 RPMI 培养基中。将细胞悬浮在各自的培养基中，得到 10 mL 体积的细胞悬浮液，最终密度为 3-6 × 104 个细胞/mL。将适当体积的阿糖胞苷溶液转移至细胞悬浮液中，并继续孵育72小时。将细胞离心并重悬于新鲜的不含阿糖胞苷的培养基中，并测定最终的细胞计数。通过细胞计数与阿糖胞苷浓度的 S 形曲线拟合来分析数据，结果表示为 IC50（抑制细胞生长至对照值 50% 的阿糖胞苷浓度）。细胞测定：在无水乙醇中制备阿糖胞苷储备溶液，并制备阿糖胞苷的系列稀释液。 CCRF-CEM 细胞悬浮在补充有 10% FBS、0.1% 庆大霉素和 1% 丙酮酸钠的 RPMI 培养基中。将细胞悬浮在各自的培养基中，得到 10 mL 体积的细胞悬浮液，最终密度为 3-6 × 104 个细胞/mL。将适当体积的阿糖胞苷溶液转移至细胞悬浮液中，并继续孵育72小时。将细胞离心并重悬于新鲜的不含阿糖胞苷的培养基中，并测定最终的细胞计数。通过细胞计数与阿糖胞苷浓度的 S 形曲线拟合来分析数据，结果表示为 IC50（抑制细胞生长至对照值 50% 的阿糖胞苷浓度）。

阿糖胞苷对急性白血病非常有效，急性白血病会导致特征性的 G1/S 阻断和同步化，并以弱剂量相关的方式延长白血病棕色挪威大鼠的生存时间，表明使用较高剂量的阿糖胞苷不会导致其死亡。对人类的抗白血病功效。阿糖胞苷 (250 mg/kg) 还会导致胎盘生长迟缓，并增加妊娠 Slc:Wistar 大鼠胎盘迷路区胎盘滋养层细胞凋亡，该细胞凋亡从治疗后 3 小时开始增加，并在 6 小时达到峰值，然后在 10 小时恢复到对照水平。 48小时，p53蛋白、p21、cyclinG1、fas等p53转录靶基因和caspase-3活性显着增强

阿糖胞苷在无水乙醇中制备为储备溶液，并且阿糖胞苷以系列稀释液制备。含有 10% FBS、0.1% 庆大霉素和 1% 丙酮酸钠的 RPMI 培养基补充有 CCRF-CEM 细胞。为了达到 3-6 × 10⁴ 细胞/mL 的最终密度，将细胞悬浮在各自的培养基中以产生 10 mL 体积的细胞悬浮液。向细胞悬液中添加适量的阿糖胞苷溶液后，将孵育过程延长整整72小时。将细胞离心并重悬于新的不含阿糖胞苷的培养基中后，获得最终的细胞计数。结果以 IC50 表示，即抑制细胞生长至对照值 50% 的阿糖胞苷浓度。通过将 S 形曲线拟合到细胞计数和阿糖胞苷浓度之间的关系来分析数据。

将不同浓度的阿糖胞苷与细胞在 37 °C 下孵育 24、48 和 72 小时。在阿糖胞苷存在下孵育 20、44 或 68 小时后，添加 10 毫升细胞增殖试剂 WST-1 溶液。与 WST-1 孵育 2 或 4 小时后，通过计算分光光度计 450 nm 处的吸光度来测量比色变化，以确定细胞的代谢活性。此外，细胞分裂时间是通过计数曙红并结合活力测试来确定的。

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.

Toxicity Summary
/HUMAN EXPOSURE STUDIES/ The principal toxicity of standard induction regimens for acute non-lymphocytic leukemia (ANLL) [including cytarabine (ARA-C) 100 mg/sq m for 7 days plus an anthracycline] is myelotoxicity, leading to death in at least 25% of cases during induction in non-selected patients. The complete remission rate is less than 35% in patients over 65 years of age, due in part to an age-related increase of myelotoxicity. The other important adverse effect of standard-dose cytarabine is gastrointestinal toxicity, especially oral mucositis, diarrhea, intestinal ulceration, ileus and subsequent Gram-negative septicaemia. Idiosyncratic reactions like exanthema, fever and elevation of hepatic enzymes are relatively frequent, but do not represent therapeutic problems. Intermittent high-dose cytarabine (3 g/sq m in 8 to 12 doses) is extremely myelosuppressive. Similarly, the gastrointestinal toxicity is formidable and dose-limiting. Severe, and sometimes irreversible, cerebellar/cerebral toxicity in 5 to 15% of courses of treatment limits the peak dose of cytarabine. The pathogenesis, prophylactic and therapeutic measures are unknown. These major toxicities are age-related and prohibitive to the use of high-dose cytarabine therapy in patients older than 55 to 60 years. Subacute noncardiogenic pulmonary edema occurs in some patients, with an incidence of about 20%, and seems to have an intriguing coincidence with precedent streptococcal septicaemia; high-dose systemic steroids may be beneficial. Corneal toxicity is very frequent in high-dose cytarabine therapy but is always reversible. It is largely preventable with prophylactic steroid or 2-deoxycytidine eyedrops. Fever, exanthema and hepatic toxicity have an incidence similar to that in standard dosage. The maximum tolerable cumulated dose of cytarabine is significantly lower when the agent is administered as a continuous infusion, due to myelosuppression and gastrointestinal toxicity. Conversely, continuous infusion may be less neurotoxic. The antileukemic effect of continuous infusion high-dose cytarabine is less well established. The only significant toxicity of low-dose cytarabine is myelosuppression. Given the generally poor condition of leukemia patients, low-dose cytarabine therapy is well tolerated, although occasional cases of diarrhoea, reversible cerebellar symptoms, peritoneal and pericardial reactions, and ocular toxicity have been reported. Continuous infusion may be more toxic than the usual intermittent dosage. It is concluded that the toxicity of the standard induction regimen for ANLL is acceptable in patients younger than 60 to 65 years with no concurrent disease. Low dose cytarabine is tolerable for virtually all ANLL patients, but the overall therapeutic efficacy still needs to be defined and compared to standard therapy in the relevant age groups.
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.

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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%

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Toxicity Data
Cytarabine syndrome may develop - it is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise.

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Interactions
GI absorption of oral digoxin tablets may be substantially reduced in patients receiving combination chemotherapy regimens (including regimens containing cytarabine), possibly as a result of temporary damage to intestinal mucosa caused by the cytotoxic agents. Plasma concentrations of digoxin should be carefully monitored in patients receiving such combination chemotherapy regimens. Use of digoxin oral elixir or liquid-filled capsules may minimize the potential interaction, since the drug is rapidly and extensively absorbed from these dosage forms. Limited data suggest that the extent of GI absorption of digitoxin (no longer commercially available in the US) is not substantially affected by concomitant administration of combination chemotherapy regimens known to decrease absorption of digoxin.
One in vitro study indicates that cytarabine may antagonize the activity of gentamicin against Klebsiella pneumoniae. Patients receiving concurrent cytarabine and aminoglycoside therapy for the treatment of infections caused by K. pneumoniae should be closely monitored; if therapeutic response is not achieved, reevaluation of anti-infective therapy may be necessary.
Limited data suggest that cytarabine may antagonize the anti-infective activity of flucytosine, possibly by competitive inhibition of the anti-infective's uptake by fungi.
The incidence of toxicity may be increased when liposomal cytarabine is used concurrently with systemic chemotherapy in patients withneoplastic meningitis. Increased neurotoxicity has been observed in patients recievingconcomitant intrathecal administration of conventionalcytarabine and other cytotoxic agents.
For more Interactions (Complete) data for CYTARABINE (15 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse ip 3779 mg/kg
LD50 Mouse oral 3150 mg/kg

[1]. Mol Pharm . 2004 Mar-Apr;1(2):112-6.

[2]. Blood . 2002 Feb 15;99(4):1373-80.

[3]. Cell Death Differ . 2003 Sep;10(9):1045-58./a >

[4]. Br J Cancer . 1988 Dec;58(6):730-3.

[5]. Biol Reprod . 2004 Jun;70(6):1762-7.

Therapeutic Uses
Antimetabolites, Antineoplastic; Antiviral Agents; Immunosuppressive Agents; Teratogens
DepoCyt (cytarabine liposome injection) is indicated for the intrathecal treatment of lymphomatous meningitis. This indication is based on demonstration of increased complete response rate compared to unencapsulated cytarabine. There are no controlled trials that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms, or increased time to disease progression, or increased survival. /Cytarabine liposome injection/
Cytarabine is indicated, in combination with other antineoplastic agents, for treatment of acute nonlymphocytic leukemia in adults and children. /Included US product label/
Cytarabine is indicated for treatment of acute lymphocytic leukemia and chronic myelocytic leukemia (blast phase). /Included in US product label/
For more Therapeutic Uses (Complete) data for CYTARABINE (10 total), please visit the HSDB record page.

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Drug Warnings
The patient's hematologic status must be carefully monitored. Leukocyte and platelet counts should be performed frequently during cytarabine therapy. The manufacturers state that leukocyte and platelet counts should be determined daily during remission induction therapy of acute leukemia. The manufacturers also recommend frequent bone marrow examinations after blast cells have disappeared from the peripheral blood.
Patients who receive myelosuppressive drugs experience an increased frequency of infections (e.g., viral, bacterial, fungal) as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs. ...Treatment with cytarabine should be initiated only with extreme caution in patients with preexisting drug-induced bone marrow suppression.
The manufacturers recommend that periodic determinations of renal function be performed in patients receiving cytarabine. Periodic determinations of hepatic function should also be performed in patients receiving cytarabine, and the manufacturers state that the drug should be used with caution and in reduced dosage in patients with poor hepatic function.
Cytarabine is contraindicated in patients with known hypersensitivity to the drug.
For more Drug Warnings (Complete) data for CYTARABINE (30 total), please visit the HSDB record page.

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Pharmacodynamics
Cytarabine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute myelogenous leukemia and meningeal leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA by multiple mechanisms, including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and incorporation into DNA. The latter mechanism is probably the most important. Cytotoxicity is highly specific for the S phase of the cell cycle.

C9H13N3O5

243.22

243.085

C, 44.45; H, 5.39; N, 17.28; O, 32.89

147-94-4

6253

White to off-white solid powder

1.9±0.1 g/cm3

529.7±60.0 °C at 760 mmHg

214 °C

274.1±32.9 °C

0.0±3.2 mmHg at 25°C

1.756

-1.78

130.83

4

5

2

17

383

4

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]

UHDGCWIWMRVCDJ-CCXZUQQUSA-N

InChI=1S/C9H13N3O5/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)/t4-,6-,7+,8-/m1/s1

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

2934.99.03.00

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)

配方 1 中的溶解度: ≥ 2.08 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (8.55 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: Saline: 30 mg/mL

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配方 5 中的溶解度: 100 mg/mL (411.15 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。