The metabolism and biliary excretion of i4C-dideoxyinosine (I4C-ddI) has been investigated using the in situ perfused rat liver (PRL) preparation. After 2 h of perfusion through the liver, approximately 7&75 per cent of the total I4C-radiolabel was recovered in the perfusion medium, less than 1 per cent was excreted in bile and 15-18 per cent was retained in the liver. Hepatic clearance of ddI was 1.5 f0.1 mlmin-' and half-life for the elimination of ddI from the medium was 22.9 f 2.0 min (n = 3). Hepatic extraction was estimated to be 7.5 per cent. HPLC analysis of the effluent perfusate indicated that ddI was metabolized to hypoxanthine, xanthine, uric acid, and to a polar metabolite which was tentatively identified as allantoin. Approximately 60-65 per cent of the ddI dose was converted to allantoin after 2 h of perfusion. Of the other three metabolites, uric acid levels increased to 2&30 per cent of the dose after 45 min and declined to about 5 per cent of the dose by the end of the perfusion period. Levels of hypoxanthine and xanthine were low and both compounds were not detected in the perfusate after 45 min post-infusion. In bile, the major peak, which accounted for about 50 per cent of the I4C-radiolabel co-eluted with the putative metabolite, allantoin (0.4 per cent of the dose). Uric acid (0.06 per cent of the dose) was the only other metabolite detected in bile. These results suggest that biliary excretion is a minor pathway for the elimination of ddI. Furthermore, ddI is rapidly cleared and metabolized by the liver to hypoxanthine, xanthine, uric acid, and to allantoin. KEY WORDS 2',3'-Dideoxyinosine (ddI) Perfused rat liver Metabolism
Introduction
A number of 2',3'-dideoxynucleosides are being evaluated for their activity against the human immunodeficiency virus (HIV), the organism implicated in acquired immunodeficiency syndrome (AIDS). Among these compounds, 2',3'-dideoxyinosine (ddI, Figure 1) is known to inhibit the infectivity of HIV in vitro at concentrations greater than 10 pM and to exhibit good therapeutic ratios in human cell lines.' The mode of action of dd1 is postulated to proceed