Cytarabine Pfizer

Cytarabine Pfizer Mechanism of Action

cytarabine

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma

Marketer:

DKSH
Full Prescribing Info
Action
Pharmacotherapeutic Group: Antineoplastic agent.
Pharmacology: Pharmacodynamics: Mechanism of Action: The exact mechanism(s) of action of cytarabine has not been fully elucidated; however it appears to act through DNA synthesis inhibition. 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. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. Extensive chromosomal damage, including chromatoid breaks, has been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. Deoxycytidine prevents or delays (but does not reverse) the cytotoxic activity. Cell culture studies have shown an antiviral effect. However, efficacy against herpes zoster or smallpox could not be demonstrated in controlled clinical trials. Cytarabine is converted intracellularly to an active metabolite (cytarabine triphosphate) which inhibits DNA synthesis. The enzyme responsible for this conversion is deoxycytidine kinase which is found predominantly in the liver and possibly the kidney. Cytarabine is inactivated by the enzyme cytidine deaminase found in the intestine, kidney and liver. The ratio of the activating enzyme (deoxycytidine kinase) to the inactivating enzyme (cytidine deaminase) in cells, determines the susceptibility of the tissue to the cytotoxic effects of cytarabine. Tissues with a high susceptibility have high levels of the activating enzyme. Cytarabine has no effect on non-proliferating cells, or on proliferating cells unless in the S or DNA synthesis phase. Thus, cytarabine is a cell cycle phase-specific antineoplastic drug.
Pharmacokinetics: Absorption: Orally, less than 20% of a dose of cytarabine is absorbed from the gastrointestinal tract and is ineffective by this route. Subcutaneously or intramuscularly, tritium labelled cytarabine produces peak plasma concentrations of radioactivity within 20 - 60 minutes and are considerably lower than those attained after intravenous administration. Continuous intravenous infusions produce relatively constant plasma levels in 8 - 24 hours.
Distribution: Cytarabine is widely distributed into tissues including liver, plasma and peripheral granulocytes. Cytarabine crosses the blood brain barrier to a limited extent and is thought to cross the placental barrier. It is not known if cytarabine is distributed into milk. Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after single intravenous injection. However, in one patient in whom cerebrospinal levels were examined after 2 hours of constant intravenous infusion, levels approached 40 percent of the steady state plasma level. With intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a first order half-life of about 2 hours. Because cerebrospinal fluid levels of deaminase are low, little conversion to ara-U was observed.
Elimination: Intravenous doses of cytarabine exhibit a biphasic elimination, with an initial distribution half-life of about 10 minutes during which time a major portion of the drug is metabolised in the liver to the inactive metabolite uracil arabinoside. The secondary elimination half-life is longer, approximately 1 - 3 hours. Metabolism occurs also in the kidneys, gastrointestinal mucosa, granulocytes and other tissues.
Excretion: Cytarabine is mainly excreted via the kidney with 70 - 80% of a dose administered by any route appearing in the urine within 24 hours; approximately 90% as the metabolite and 10% as unchanged drug.
Immunosuppressive Action: Cytarabine is capable of obliterating immune responses in man during administration with little or no accompanying toxicity. Suppression of antibody responses to E. coli-V1 antigen and tetanus toxoid has been demonstrated. This suppression was obtained during both primary and secondary antibody responses. Cytarabine also suppressed the development of cell-mediated immune responses such as delayed hypersensitivity skin reaction to dinitrochlorobenzene. However, it had no effect on already established delayed hypersensitivity reactions. Following 5-day courses of intensive therapy with cytarabine the immune response was suppressed, as indicated by the following parameters: macrophage ingress into skin windows; circulating antibody response following primary antigenic stimulation; lymphocyte blastogenesis with phytohaemaglutinin. A few days after termination of therapy there was a rapid return to normal.
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