Biotransformation of 9-β-d-arabinofurano-syladenine by rat and human erythrocytes

Abstract

Studies were performed to test whether 9-β- d-arabinofuranosyladenine (ara-A) would accumulate in erythrocytes as a result of phosphorylation to the nucleotide level. When [ 3H]ara-A was incubated with whole blood from rat, monkey or man for 2 hr at 37°, the drug rapidly equilibrated between erythrocytes and plasma but did not concentrate in the cells. Incubation of [ 3H]ara-A with rat and human erythrocyte lysates for 2 hr followed by Chromatographie analysis showed that 2–5 per cent of ara-A was converted to nucleotides. In contrast, 10–35 per cent of [ 14C]adenosine was converted to adenine nucleotides under the same conditions. Incubation of [ 3H]ara-A with human erythrocyte lysates for 18 hr resulted in a conversion of approx. 40 per cent of the labeled drug to nucleotides. Additional chromatography revealed, however, that the nucleotide fraction contained almost no arabinosyl nucleotides. Rather, 90 per cent of the label in the nucleotide fraction was identified as IMP. These results indicate that only a minor amount, if any, of ara-A was phosphorylated by erythrocyte enzymes to yield arabinosyl nucleotides. An alternative pathway converted much of the labeled drug to ribosyl nucleotides via the deamination of ara-A to ara-hypoxanthine, cleavage to hypoxanthine and conversion of the free hypoxanthine to IMP.