Intracellular metabolism of zidovudine and stavudine in combination.

To the Editor-We read with interest the findings of Merrill et at. [1] that for zidovudine-resistant isolates of human immunodefi-ciency virus type 1 (HIV-1), the addition of zidovudine to stavu-dine antagonized the antiviral effect of stavudine in vitro as judged by inhibition of p24 antigen production. The combination of the two drugs was, however, synergistic against zidovudine-sensitive strains of HIV-1. These observations may be explained by interactions affecting intracellular phosphorylation of these agents. tion of zidovudine (mean, 5.79 pmol/Iu" cells), a reduction of some 41 % (table 1). Higher ratios of zidovudine to stavudine of 1:1 and 10: 1 resulted in reductions of 67% and 83%, respectively. On the other hand, zidovudine phosphorylation remained relatively unaffected by combination with stavudine (maximum inhibition of 23% at a concentration ratio of 1000; table 1). These observations are in keeping with data suggesting that thymidine kinase has a 600-fold lower affinity for stavudine than for zidovudine [2]. The combination of both nucleoside analogues thus results in diminished phosphorylation of stavudine without significantly affecting zidovudine phosphorylation. Table 1. Phosphorylation of zidovudine (ZDV) and stavudine (d4T) alone and in combination.