Differential antiviral activities and intracellular metabolism of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine in human cells.

Dideoxynucleosides such as 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI) can effectively inhibit the replication of human immunodeficiency virus (HIV) in T lymphoid cells. There is evidence that HIV can infect and replicate in other cells including monocytoid cells and macrophages. The present study compared the antiretroviral activities of ddI and AZT in three lineages of human cells, i.e., MOLT4 (T lymphocytoid, CD4+), U937 (monocytoid, CD4+), and HT1080 (fibroblastoid, CD4-) cells. Feline leukemia virus, a retrovirus that causes immunodeficiency in cats, was used to infect the cells. The drug concentrations needed to reduce the viral p27 antigen titers in cell lysates by 50% (IC50s) were determined. The data show that AZT and ddI inhibited viral replication in all three cell lines. The IC50s of AZT were 0.02, 1.75, and 2.31 microM in MOLT4, HT1080, and U937 cells, respectively. For ddI, the IC50s were 4.31, 9.52, and 43.5 microM, respectively. These data indicate differential antiviral activities of ddI and AZT in the different cells with the following rank order of drug sensitivity: MOLT4 > HT1080 > U937. A study of the intracellular metabolism of [3H]AZT and [3H]ddI shows that the antiretroviral activities of AZT and ddI in the three cell lines correlated with the levels of their intracellular triphosphate metabolites.

Percutaneous absorption of 2',3'-dideoxyinosine in rats.

This study explored the topical route for administering of 2',3'-dideoxyinosine (ddI), a nucleoside analog used for treating patients with acquired immunodeficiency syndrome. A dose of ddI (approximately 180 mg/kg) dispersed in approximately 1 g ointment base was applied, with or without occlusion, to the back of high follicular density (HFD) and low follicular density (LFD) rats. The systemic ddI clearance was determined using a concomitant administration of an intravenous tracer dose of [3H]ddI. At 24 hr, the experiment was terminated and skin sections at the application site were removed. After topical application, average plateau plasma levels of about 0.6 microgram/ml were achieved within 1 to 2 hr and maintained for 24 hr. Occlusion gave a more uniform plasma profile but did not increase the bioavailability. The systemic bioavailability in HFD and LFD rats was about the same at 33%. In addition, a depot of about 16% of the dose was recovered by rinsing the application area and extracting the drug from the excised application site. These data indicate that about 50% of the dermal dose penetrated the skin barrier in 24 hr. The similar bioavailability in the HFD and LFD rats further suggests an unimportant role for the transfollicular absorption route for ddI. The effect of a mixture of penetration enhancers, Azone and propylene glycol (5:95), was studied in HFD rats. Coadministration of ddI with the enhancers did not increase the ddI bioavailability. However pretreatment and coadministration with the enhancers significantly increased the bioavailability to 62%, which is a conservative estimate because the plasma drug level was still at a plateau when the experiment was terminated at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonlinear disposition of intravenous 2',3'-dideoxyinosine in rats.

The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses. ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phosphorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.