ISSN:
1573-904X
Keywords:
Caco-2 cells
;
intestinal absorption
;
lipophilicity
;
solvation energy
;
hydrogen bonding
;
bioavailability
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. The effects of structural modifications on the membrane permeability of angiotensin II (Ang II) receptor antagonists and the usefulness of in vitro and in situ intestinal absorption models in predicting in vivo absorption or bioavailability were investigated. Methods. Intestinal permeability was determined in vitro using Caco-2 cell monolayers and in situ using a perfused rat intestine method. Several physicochemical parameters were either measured or computed, and correlated with intestinal permeation. Results. Permeation coefficients (Pa) across Caco-2 cell monolayers correlated well with both in situ absorption rate constants (ka) and in vivo bioavailability or % absorption. For these Ang II antagonists, Pa values larger than 3 × 10−6 cm sec−1 and in situ ka values of 2 × 10−4 min−1 cm−1 or above were associated with good in vivo absorption. Structural modifications at the R5 position, where a COOH group was substituted with either a CHO or CH2OH group, enhanced the permeability of the Ang II receptor antagonists up to 100-fold. There were good correlations between permeability and log P(octanol/buffer), log PHPLCcharge, solvation/desolvation energy and assigned hydrogen bonding potential. Conclusions. The correlations obtained in this study indicate that both the Caco-2 cell model and the in situ perfused rat intestine could be used to predict intestinal absorption in vivo. Structural modifications of the Ang II antagonists had a significant impact on the intestinal permeability. Charge, solvation energy, and hydrogen bonding are predominant determinants of intestinal permeability and oral bioavailability of these compounds.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1016086930019
Permalink
