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.
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 (approximately pH 6) than in the ileum or colon (pH > or = 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.
Sinko
P J
PJ
Department of Pharmaceutics, College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08855, USA. sinko@rci.rutgers.edu
Sutyak
J P
JP
Leesman
G D
GD
Hu
P
P
Makhey
V D
VD
Yu
H
H
Smith
C L
CL
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D003106:Colon / Q000378:metabolism; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D004386:Duodenum / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption; D008297:Male; D010477:Perfusion; D014018:Tissue Distribution
D019380:Anti-HIV Agents; D016049:Didanosine