ZALCITABINE (DDC) PHOSPHORYLATION AND DRUG-INTERACTIONS

Zalcitabine (2',3'-dideoxycytidine; ddC) is an inhibitor of HIV reverse transcriptase. The intracellular metabolism of ddC in peripheral blood mononuclear cells (PBMCs), U937 cells and Molt 4 cells were investigated, and phosphate metabolites were determined by on-line radiometric HPLC. Comparable levels of all three ddC phosphate metabolites were formed in PHA-stimulated PBMCs, U937 cells and Molt 4 cells. Zidovudine (ZDV), didanosine (ddl) and stavudine (d4T) had no significant effect on ddC (0.06 mu M) phosphorylation in PBMCs whereas the endogenous nucleoside, cytidine decreased phosphorylation in a concentration-dependent manner (e.g. 41% inhibition of total phosphate formation at 6 mu M cytidine, 85% inhibition at 60 mu M). The cytotoxic anticancer drug doxorubicin caused a decrease in ddC phosphorylation in U937/Molt 4 cells (e.g. 56% inhibition of total phosphate formation in U937 cells; 55% in Molt 4 cells at a doxorubicin concentration of 60 mu M), whilst the antiviral agent ribavirin exhibited no inhibitory effects.