Distribution of 2-chloro-2 '-deoxyadenosine, 2-chloro-2 '-arabino-fluoro-2'-deoxyadenosine, Fludarabine and Cytarabine in mice: a whole-body autoradiography study

The distribution characteristics of tritiated nucleoside analogs, 2-chloro- 2'-deoxyadeonosine (CdA), 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAF dA), 2-fluoroarabinosyladenine (F-ara-A) and cytosine arabinoside (ara-C) w ere compared in mice using whole-body autoradiography. CdA, CAFdA and F-ara -A have quite similar molecular structures, but they differ substantially i n clinical activity as well as the side effects. Eight mice were injected i ntravenously in couples. One mouse from each pair was killed 20 min postinj ection and the other mouse from each pair 4 h after the injection. The dist ribution of the label was then analyzed by whole-body autoradiography. The distribution of the nucleoside analogs was rapid and uniform. High conc entrations were found in highly perfused organs. After 4 h the overall conc entration had decreased but relatively high activities were found in the sk in for CdA and CAFdA, in the thymus for ara-C and the bone marrow for CdA. Both CdA and CAFdA were found in the brain, but the concentration was surpr isingly lower after 4 h for CAFdA, a lipophilic and more stable analog as c ompared to CdA. There was an uptake of CdA, F-ara-A and CAFdA in the skin. There were signs of retention of ara-C in parts of the thymus. The present investigations indicate that the nucleoside analog transport to the brain in mice is not primarily dependent upon passive diffusion over a lipophilic barrier, but suggestive of a specific transport mechanism.