Gastrointestinal and hepatic first-pass elimination of 2',3'-dideoxyinosine in rats

We previously reported a > 80% presystemic loss of 2',3'-dideoxyinosine (ddl) in rats after an oral dose. The present study investigated the extent of drug loss due to incomplete absorption and presystemic elimination by intestinal wall, liver and intestinal microflora. In vitro metabolism by tissue homogenates showed that the extraction by liver, duodenum, jejunum and ileum was 19.0, 0.5, 1.8 and 1.4%, respectively. Hence, metabolism by the intestinal wall contributed less to the first-pass metabolism than the liver. The in vivo first-pass elimination was determined by infusing ddl into the liver and different parts of the intestinal tract. The in vivo extractions of 12 and 200 mg kg-1 of ddl doses by the liver were 23 and 5%, indicating a concentration-dependent liver metabolism. The in vivo liver extraction at the low dose was similar to the in vitro extraction. The in vivo extraction was 10% in the duodenum and 73% in the ileum. The significantly higher in vivo intestinal extractions compared to the in vitro extractions indicate a loss due to factors in addition to intestinal wall enzyme metabolism. Incomplete absorption was ruled out, based on the undetectable excretion of ddl in feces after duodenal or ileal infusion. A 14% w/v solution of intestinal contents degraded ddl by 18 and 38% over 2 and 24 hr, respectively, at 37 degrees C. By linear extrapolation, a 100% w/v enzyme solution would degrade the entire dose within 1.5 hr.(ABSTRACT TRUNCATED AT 250 WORDS)