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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
Author(s) -
Sinko Patrick J.,
Sutyak John P.,
Leesman Glen D.,
Hu Peidi,
Makhey Vijaya D.,
Yu Hongshi,
Smith Curtis L.
Publication year - 1997
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/(sici)1099-081x(199711)18:8<697::aid-bdd57>3.0.co;2-z
Subject(s) - duodenum , jejunum , ileum , pharmacokinetics , in vivo , chemistry , small intestine , intestinal permeability , bolus (digestion) , phenol red , oral administration , pharmacology , gastroenterology , physiologically based pharmacokinetic modelling , medicine , biology , biochemistry , chromatography , microbiology and biotechnology
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.