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Metabolism of 14 C‐2′,3′‐dideoxyinosine by the in situ perfused rat liver preparation
Author(s) -
Tay Lee K.,
Papp Eugene A.,
Timoszyk Julita
Publication year - 1991
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510120406
Subject(s) - allantoin , hypoxanthine , metabolite , uric acid , metabolism , xanthine , chemistry , perfusion , urine , medicine , endocrinology , chromatography , biochemistry , pharmacology , biology , enzyme
The metabolism and biliary excretion of 14 C‐dideoxyinosine ( 14 C‐ddI) has been investigated using the in situ perfused rat liver (PRL) preparation. After 2h of perfusion through the liver, approximately 70–75 per cent of the total 14 C‐radiolabel was recovered in the perfusion medium, less than 1 per cent was excreted in bile and 15–18 percent was retained in the liver. Hepatic clearance of ddI was 1·5 ± 0·1 ml min −1 and half‐life for the elimination of ddI from the medium was 22·9 ± 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 2h of perfusion. Of the other three metabolites, uric acid levels increased to 20–30 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 14 C‐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.