Cytarabine

Structural formula
General
Non-proprietary name	Cytarabine
other names	araC (short code); Arabinosylcytosine; 1- β - D -arabinofuranosylcytosine; Cytosine- β - D -arabinofuranoside; 4-Amino-1 - [(2 R , 3 S , 4S , 5 R ) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl] pyrimidin-2-one;
Molecular formula	C 9 H 13 N 3 O 5
Brief description	colorless solid
External identifiers / databases
EC number	205-705-9
ECHA InfoCard	100.005.188
PubChem	6253
ChemSpider	6017
DrugBank	DB00987
Wikidata	Q180983
Drug information
ATC code	L01 BC01
Drug class	Cytostatic
Mechanism of action	Antimetabolite
properties
Molar mass	243.17 g mol −1
Physical state	firmly
Melting point	212-213 ° C
solubility	soluble in water
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 317-361
	P: 280
Toxicological data	> 5 mg kg −1 ( LD 50 , rat , iv ) ; > 500 mg kg −1 ( LD 50 , rat , oral ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Cytarabine (araC) is an isomer of the nucleoside cytidine . It consists of a furanose (sugar) and the cytosine . It contains - in contrast to most nucleosides - instead of β- D -Ribofuranose the β- D -Arabinofuranose and thus belongs to the group of arabinosyl nucleosides . It is used as a cytostatic (antimetabolite) for the growth-inhibiting treatment of cancer . In addition, cytarabine also has virus-inhibiting properties, but is only rarely used as an antiviral agent .

Mechanism of action

Cytarabine acts as the wrong building block in DNA . After conversion (phosphorylation) into its active form, cytosine arabinoside triphosphate, it is incorporated into the DNA instead of the nucleotide cytidine triphosphate during DNA replication. In addition, the DNA repair mechanisms are also blocked. Cytarabine is almost exclusively cytotoxic during the S phase of the cell cycle .

Pharmacokinetics

Uptake and bioavailability

Less than 20% of the oral dose of cytarabine is absorbed into the bloodstream. When administered intravenously or subcutaneously, cytarabine can pass through the liquor ( liquor-to- plasma ratio 14% i.v. bolus, 40–60% i.v. infusion or s. C. Injection). The plasma protein binding of cytarabine is 13%. The volume of distribution of cytarabine was determined to be 3.0 ± 1.9 l / kg body weight.

Metabolism (metabolism)

Cytarabine is metabolized to cytosine arabinoside triphosphate (active) and uracil arabinoside (inactive) in the liver.

Elimination

Extensive metabolism via cytosine deaminases in the liver and kidneys.

application areas

Cytarabine is primarily used to treat acute myeloid leukemia (AML) in children and adults. In AML treatment, cytarabine is one of the most important cytostatics. In addition to AML, cytarabine is also used to treat acute lymphoblastic leukemia (ALL) in children and adults.

The effectiveness of cytarabine in acute leukemia was first described in a major scientific publication in 1968. In this study 116 patients with relapsed acute leukemia (15 ALL, 77 AML or acute biphenotypic leukemia) were given continuous cytosine infusions over 12 or 24 hours at a dose of 30 mg / m² body surface area (BSA) per day for one week, or alternatively treated as 1-hour infusions of 50 or 100 mg / m² BSA and day. The average remission rate for AML was around 25%, which was higher than for any other drug known at the time. The 1-year survival, especially of the patients who responded to the drug, was markedly improved. Cytarabine has remained a basic component of almost every AML chemotherapy to this day. The "7 + 3 scheme" is particularly common (7 days of cytosine 100 mg / m² / day continuous infusion and an additional anthracycline on 3 days ).

A special feature of cytarabine is the ability to cross the blood-brain barrier, especially when high doses are administered (> 1000 mg / m ² body surface area per single dose) and thus to be effective in the brain against leukemia cells. Cytarabine can also be administered directly into the cerebral fluid ( intrathecal administration) alone or in combination with prednisone and methotrexate (so-called triple ).

Adults

Acute myeloid leukemia (AML)
Acute lymphocytic leukemia (ALL)
Myelodysplastic Syndrome (MDS)
Non-Hodgkin lymphoma (NHL)

Children and young people

Acute myeloid leukemia (AML)
Acute lymphocytic leukemia (ALL). Cytarabine can be used in the treatment of ALL both in the case of the initial illness and in the event of a relapse (relapse).
Myelodysplastic Syndrome (MDS)
Non-Hodgkin lymphoma (NHL)

Dose and administration

Adults

Acute myeloid leukemia (AML)
Acute lymphocytic leukemia (ALL)
Myelodysplastic Syndrome (MDS)
Non-Hodgkin lymphoma (NHL)

Children and young people

Acute myeloid leukemia (AML)

Acute lymphocytic leukemia (ALL). Cytarabine is mainly used in combination with other cytostatics in high doses in the consolidation treatment of ALL. The dosage used here is 3000 mg / m ² body surface area per single dose as i. v. Infusion with a running time of 3 hours. 4 single doses of cytarabine are administered within 48 hours at intervals of 12 hours. This combination chemotherapy is also known as the HIDAC block with the simultaneous use of asparaginase after the end of the cytarabine infusions .

Myelodysplastic Syndrome (MDS)

Non-Hodgkin lymphoma (NHL). Cytarabine is used in high doses, especially in combination with other cytostatics, in the consolidation treatment of highly malignant B- and T-cell non-Hodgkin lymphomas in children and adolescents. A dosage used in the treatment of highly malignant T-cell NHL is 3000 mg / m ² body surface area per single dose as i. v. Infusion with a running time of 3 hours. 4 single doses of cytarabine are administered within 48 hours at intervals of 12 hours. This combination chemotherapy is also known as the HIDAC block with the simultaneous use of asparaginase after the end of the cytarabine infusions .

Side effects

Bone marrow depression ( myelotoxicity ) with anemia , thrombopenia and leukopenia ( neutropenia ). As a rule, the higher the dose of cytarabine, the more severe the bone marrow depression.

Neurotoxicity. High doses of cytarabine can cause (temporary) damage to the cerebellum ( cerebellitis ). In the case of intrathecal administration, non-infectious (chemically caused) irritation (inflammation) of the meninges is possible ( meningitis , arachnoiditis ).

Conjunctivitis ( conjunctivitis ). At high doses of cytarabine, conjunctivitis can occur.

Nausea and vomiting

Damage to the mucous membrane ( mucositis )

Hair loss (alopecia)

Shortness of breath and acute respiratory distress syndrome (dyspnea and ARDS)

Liver damage (hepatotoxicity)

Contraindications (contraindications)

Trade names

Monopreparations

Alexan (D, A), ARA-cell (D), Cytosar (CH), DepoCyte (D, A, CH), various generics (D, A)

literature

SS Cohen: The mechanisms of lethal action of arabinosyl cytosine (araC) and arabinosyl adenine (araA). In: Cancer. 40 (1 Suppl), Jul 1977, pp. 509-518. PMID 328134 .

Individual evidence

↑ ^a ^b ^c data sheet 1-β-D-arabinofuranosylcytosine (PDF) from Calbiochem, accessed on December 8, 2015.
↑ ^a ^b Data sheet Cytosine β-D-arabinofuranoside from Sigma-Aldrich , accessed on November 4, 2013 ( PDF ).
↑ ^a ^b Entry on cytarabine in the ChemIDplus database of the United States National Library of Medicine (NLM)
^ RR Ellison, JF Holland, M. Weil, C. Jacquillat, M. Boiron, J. Bernard, A. Sawitsky, F. Rosner, B. Gussoff, RT Silver, A. Karanas, J. Cuttner, CL Spurr, DM Hayes, J. Blom, LA Leone, F. Haurani, R. Kyle, JL Hutchinson, RJ Forcier, JH Moon: Arabinosyl cytosine: a useful agent in the treatment of acute leukemia in adults. In: Blood. 32 (4), 1968, pp. 507-523. (PDF)
↑ U. Krug, T. Büchner, WE Berdel, C. Müller-Tidow: Treatment of elderly patients with acute myeloid leukemia. In: Dtsch Arztebl. 108 (51-52), 2011, pp. 863-870. (PDF)

Web links

Entry for cytarabine in the Human Metabolome Database (HMDB) , accessed October 16, 2013.
BC Cancer Agency information page on cytarabine as of 2006. Freely accessible.

[Merck-1] ta sheet 1-β-D-arabinofuranosylcytosine (PDF) from Calbiochem, accessed on December 8, 2015.

[Sigma-2] Data sheet Cytosine β-D-arabinofuranoside from Sigma-Aldrich , accessed on November 4, 2013 ( PDF ).

[ChemIDplus-3] Entry on cytarabine in the ChemIDplus database of the United States National Library of Medicine (NLM)

[4] RR Ellison, JF Holland, M. Weil, C. Jacquillat, M. Boiron, J. Bernard, A. Sawitsky, F. Rosner, B. Gussoff, RT Silver, A. Karanas, J. Cuttner, CL Spurr, DM Hayes, J. Blom, LA Leone, F. Haurani, R. Kyle, JL Hutchinson, RJ Forcier, JH Moon: Arabinosyl cytosine: a useful agent in the treatment of acute leukemia in adults. In: Blood. 32 (4), 1968, pp. 507-523. (PDF)

[5] U. Krug, T. Büchner, WE Berdel, C. Müller-Tidow: Treatment of elderly patients with acute myeloid leukemia. In: Dtsch Arztebl. 108 (51-52), 2011, pp. 863-870. (PDF)