Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by injection int + some more technical info; as a deoxycytidine analogue it requires intracellular phosphorylation by deoxycytidine kinase to the active triphosphate metabolite ara-CTP, which accumulates in S-phase cells, competes with dCTP for incorporation into DNA, inhibits DNA polymerase and causes chain termination and impaired DNA repair. Cytarabine is administered by intravenous bolus, continuous infusion, subcutaneous injection or by intrathecal injection for CNS prophylaxis or treatment. Systemic clearance is rapid because of extensive deamination by cytidine deaminase to arabinosyluracil (Ara-U), giving a short plasma half-life for the parent drug while intracellular ara-CTP persists longer in target cells. Dose adjustments are required for intensive high-dose regimens and in patients with impaired hepatic function or other comorbidities that alter metabolism or bone marrow reserve.
Parent: Cytarabine
Parent: Cytarabine
The principal related compound and major degradation product is arabinosyluracil (Ara-U), formed by cytidine deaminase mediated deamination; other monitored impurities include free cytosine, sugar degradation products and small amounts of synthetic byproducts that may arise during manufacture. Typical quality control acceptance criteria applied to the API and injectable formulation are conservative: individual unspecified impurities are commonly limited to 0.2 to 0.5 percent (w/w) by validated HPLC methods, the identified deamination product Ara-U is frequently limited to 0.5 to 1.0 percent depending on the monograph and manufacturing route, and total impurities are generally controlled to be below about 1.0 to 2.0 percent. Residual solvents and elemental impurities are controlled separately to ICH limits and particulate and endotoxin specifications apply for parenteral products.
Cytarabine is used primarily to induce remission and treat relapsed disease in hematologic malignancies including AML and ALL; it is also used in certain cases of CML and non-Hodgkin’s lymphoma and for intrathecal treatment or prophylaxis of central nervous system involvement.
The primary dose limiting toxicity is myelosuppression, most notably neutropenia and thrombocytopenia, which increases infection and bleeding risk; at high doses or in susceptible patients neurotoxicity, especially cerebellar dysfunction, and severe mucositis are important toxicities to monitor.
Acute effects such as nausea, vomiting and transient hepatic enzyme elevations can occur within hours to days; mucositis and gastrointestinal toxicity generally appear within several days; hematologic toxicities are typically delayed, with nadirs for neutrophils and platelets occurring approximately 7 to 14 days after exposure; neurotoxic effects with high-dose regimens may appear during or within days of treatment.
In AML cytarabine acts as a deoxycytidine analogue prodrug that is phosphorylated intracellularly to ara-CTP, the active metabolite, which preferentially accumulates in S-phase leukemic blasts, competitively inhibits DNA polymerases, becomes incorporated into DNA causing chain termination and blocks DNA synthesis and repair, ultimately triggering apoptosis in rapidly dividing myeloblasts.
