Uracil arabinoside

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. 

Resistance Resistance to ara-C may result from a defect in the transport process, a change in phosphorylating enzymes, or an increased pool of the natural dCTP nucleotide. Increased deamination to uracil arabinoside, ara-U, a pharmacologically inactive metabolite, can also cause resistance. 

Pharmacokinetics Ara-C is not effective when given orally because of its deamination to the noncytotoxic uracil arabinoside (ara-U) by cytidine deaminase in the intestinal mucosa. Given IV, it distributes throughout the body, but does not penetrate the CNS in sufficient amounts to be effective against meningeal leukemia. However, it may be injected intrathecally. Ara-C undergoes exten-... 

The distribution and disposition of a drug in the body result from a complex set of physiological processes and biochemical interactions. In principle, it is possible to describe these processes and interactions in mathematical terms and, if sufficient data are available, to predict the time course of drug and metabolite(s) in different species and at specific anatomic sites (15). A physiological pharmacokinetic model was developed to predict the deamination of cytosine arabinoside (ARA-C) in humans from enzyme parameters determined from homogenates of human tissue (16). ARA-C is converted to its inactive metabolite, uracil arabinoside (ARA-U) by cytidine deaminase, the activity of which varies substantially among tissues. 

Cytarabine is a pyrimidine nucleoside that is used to treat acute myelogenous leukemia and lymphocytic leukemias. It is activated intracellularly by deoxycytidine kinase to phosphorylated nucleotides that interfere with DNA synthesis in the S phase of the cell, and is rapidly deaminated intracellularly to the inactive metabolite uracil arabinoside. 

Cytarabine may be synthesized by the acetylation of uracil arabinoside followed by treatment with phosphorus pentasulphide and subsequent heating with ammonia. 

Uracil arabinoside (R H) Uracil arabinotide (R = HgOaP) (inactive)... 

We decided to apply a microbial enzyme that catalyzes the trans-arabinosylation reaction, as shown in Fig. 1. The enzyme substrate uracil arabinoside (ara-U) can be prepared from uridine through reaction with ethylene carbonate followed by the hydrolysis of cydo-uridine (cyclo-U) by add. )... 

Cytosine arabinoside is enzymatically deaminated in the liver. The resulting product, uracil arabinoside, no longer possesses antileukaemia or antiviral activity [291, 292, 340, 341]. A variety of cytosine derivatives have been studied as deaminase inhibitors. The most active of these was a 4-hydroxylamino derivative, iV -hydroxy-5-methyl-2 -deoxycytidine [342]. 

This enzyme is found in various animal tissues and that from sheep liver has been purified 280-fold 11). Both cytidine and deoxycytidine are deaminated, as are the 5-halogen derivatives (e.g., 5-fluoro-deoxycytidine). Cytosine, cytidylate, and deoi i idylate are not deaminated by this enzyme. Cytosine arabinoside (iHS-D-arabinofurano lcytosine), which has an important use in the treatment of human neoplastic disease, is a substrate for cytidine deaminase in the human, this compound is rapidly deaminated to yield the inactive uracil arabinoside 12). Cytidine deaminase is very active in E. ccli and S. typhimwrium, but is absent from yeasts and lactobacilli (7). The E. coli enzyme has been partly purified IS) and has a specificity similar to that of the animal enzyme. The E. coli enzyme deaminates 5-methyldeoxycytidine, enabling this compound to support the growth of a thymine-requiring E. coli mutant 11. ... 

After administration of 50 mg/kg, drug serum levels are depleted in an apparently haphazard fashion in relation to body size. The monkey and man metabolize the drug at a rate greater than any other species studied. However, in this instance there is a reasonable explanation for this deviation. Cytosine arabinoside is metabolized to uracil arabinoside under control of a pyrimidine nucleoside deaminase. The enzyme has a unique distribution in tissues and animal... 

Paw, B., and Misztal, G. (1995). Chromatographic analysis (TLC) of uracil arabinoside, cytosine arabinoside, uracil, and cytosine in human plasma. Acta Pol. Pharm. 52 455-457. 

Alternative dual-column analyses of the cytosine and uracil arabinosides (using reversed-phase then cation-exchange media), and of riboxamide (on silica then reversed-phase media both coated with hexadecyltrimethylammoniiim bromide), have been developed to enable the desired separation of these components from other constituents in biological samples. 

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

Keith (1995) presented reference maps of mobilities of modified ribonucleotides and nucleosides separated by two-dimensional TLC on cellulose. Paw and Misztal (1995) isolated cytosine, uracil, and their arabinosides from human plasma by solid-phase extraction and Adsobex minicolumns and separated them by horizontal and ascending TLC in various mobile phases. 

---