Oral absorption of anti- AIDS nucleoside analogues. 3. Regional absorption and in vivo permeability of 2′, 3′ - dideoxyinosine in an intestinal–vascular access port (IVAP) dog model
✍ Scribed by Patrick J. Sinko; John P. Sutyak; Glen D. Leesman; Peidi Hu; Vijaya D. Makhey; Hongshi Yu; Curtis L. Smith
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 389 KB
- Volume
- 18
- Category
- Article
- ISSN
- 0142-2782
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✦ Synopsis
The absolute oral and regional intestinal bioavailabilities (BAs) and pharmacokinetics (PK) of 2 H , 3 H -dideoxyinosine (ddI), a nucleoside analog used in the treatment of human immunode®ciency virus (HIV) infection, were investigated in an in vivo intestinal± vascular access port (IVAP) dog model. The mean (AESD) 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 unbuered solutions containing 250 mg ddI into the duodenum, ileum, and colon of IVAP beagle dogs, respectively. The BA of the orally administered Videx 2 250 mg buered chewable tablets was 44´9+1´6%. ddI absorption and disposition PK were modeled by simultaneously ®tting intravenous, oral, and intestinal plasma level versus time data using a physiologically based PK model. The region-speci®c 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 5 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 signi®cant contributing factor to the high degree of absorption variability reported for ddI.