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The absolute oral and regional intestinal bioavailabilities (BAs) and pharmacokinetics (PK) of 2', 3'-dideoxyinosine (ddI), a nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection, were investigated in an in vivo intestinal–vascular access port (IVAP) dog model. The mean (±SD) absolute regional intestinal BAs of ddI were 49·6±8·8, 42·7±7·9, and 13·6±5·4% after the bolus administration of unbuffered solutions containing 250 mg ddI into the duodenum, ileum, and colon of IVAP beagle dogs, respectively. The BA of the orally administered Videx^™ 250 mg buffered chewable tablets was 44·9±1·6%. ddI absorption and disposition PK were modeled by simultaneously fitting intravenous, oral, and intestinal plasma level versus time data using a physiologically based PK model. The region-specific apparent absorption rates followed the rank order duodenum>ileum>colon. Apparent regional in vivo intestinal permeabilities correlated well with previously determined regional permeabilities in rats. The intestinal pH was monitored using a radiotelemetric pH monitoring system since ddI is unstable in an acidic environment. While the pH was found to be lower in the duodenum and proximal jejunum (~pH 6) than in the ileum or colon (pH≥7·0), ddI is reasonably stable across the entire pH range of the dog small intestine. These studies demonstrate that the regional reduction in ddI BA is consistent with a reported distal reduction in intestinal permeability and appears to be a significant contributing factor to the high degree of absorption variability reported for ddI. © 1997 John Wiley & Sons, Ltd.

The absolute oral and regional intestinal bioavailabilities (BAs) and pharmacokinetics (PK) of 2′, 3′‐dideoxyinosine (ddI), a nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection, were investigated in an in vivointestinal–vascular access port (IVAP) dog model. The mean (±SD) absolute regional intestinal BAs of ddI were 49·6±8·8, 42·7±7·9, and 13·6±5·4% after the bolus administration of unbuffered solutions containing 250 mg ddI into the duodenum, ileum, and colon of IVAP beagle dogs, respectively. The BA of the orally administered Videx™250 mg buffered chewable tablets was 44·9±1·6%. ddI absorption and disposition PK were modeled by simultaneously fitting intravenous, oral, and intestinal plasma level versus time data using a physiologically based PK model. The region‐specific apparent absorption rates followed the rank order duodenum>ileum>colon. Apparent regional in vivointestinal permeabilities correlated well with previously determined regional permeabilities in rats. The intestinal pH was monitored using a radiotelemetric pH monitoring system since ddI is unstable in an acidic environment. While the pH was found to be lower in the duodenum and proximal jejunum (∼pH 6) than in the ileum or colon (pH≥7·0), ddI is reasonably stable across the entire pH range of the dog small intestine. These studies demonstrate that the regional reduction in ddI BA is consistent with a reported distal reduction in intestinal permeability and appears to be a significant contributing factor to the high degree of absorption variability reported for ddI. © 1997 John Wiley & Sons, Ltd.