Cytarabine metabolism

The drug is metabolized rapidly in the liver, kidney, intestinal mucosa, and even red blood cells. Therefore it has a plasma half-life of only 10 min after bolus intravenous application. The major metabolite, uracil arabinoside (ara-U), can be detected in the blood shortly after cytarabine administration. About 80% of the dose is excreted in the urine within 24 h, with less than 10% appearing as cytarabine the remainder is ara-U. After continuous infusion, cytarabine levels in the liquor (cerebro-spinal fluid) approach 40% of that in plasma. Continuous infusion schedules allow maximal efficiency, with uptake peaks of 5-7 pM. It can be administered intrathecally as an alternative to methotrexate. 

Although the effects of various schedules are not always predictable, drugs that are rapidly metabolized, excreted, or both, especially if they are phase specific and thus act on only one portion of the cell cycle (e.g., cytarabine), appear to be more effective when administered by continuous infusion or frequent dose fractionation than by high-dose intermittent therapy. On the other hand, intermittent high-dose treatment of Burkitt s lymphoma with cyclophosphamide is more effective than fractionated treatment, since cyclophosphamide acts on all phases of the cell cycle and almost all of the tumor cells in that disease are actively proliferating. 

Cytarabine (ara-C) is an S phase-specific antimetabolite that is converted by deoxycytidine kinase to the 5 -mononucleotide (ara-CMP). Ara-CMP is further metabolized to the diphosphate and triphosphate metabolites, and the ara-CTP triphosphate is felt to be the main cytotoxic... 

Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis interference with the formation of DNA and RNA and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia. 

CYTARABINE AZATHIOPRINE t risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis Additive myelotoxic effects. Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity Avoid co-administration... 

The toxicity of antimetabolites is, as expected, due to their incorporation into the metabolism of normal cells, which is nearly identical to that of the malignant cells that they were designed to injure. The normal cells injured most severely are the rapidly proliferating cells of the bone marrow, the lymphoid system, and the GI epithelium. Thus, the common toxicities are bone marrow depression, nausea and vomiting, diarrhea, and mucositis. Cytarabine and pentostatin can cause conjunctivitis. Capecitabine and prolonged use of fluorouracil or cytarabine can cause cerebellar ataxia and the hand-foot syndrome, that is, palmar-plantar erythrodysesthesia or acral erythema. Pentostatin and high-dose methotrexate can cause renal toxicity. 

Cytarabine (Ara-C) S-phase-specific Metabolized to ara-CTP, which is incorporated into DNA. Acts as a chain terminator and inhibits DNA polymerase. ... 

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