Effects of structural modifications on the intestinal permeability of angiotensin II receptor antagonists and the correlation of in vitro, in situ, and in vivo absorption.
OBJECTIVE
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 x 10(-6) cm sec-1 and in situ ka values of 2 x 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 PHPLC, charge, 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.
Ribadeneira
M D
MD
The DuPont Merck Pharmaceutical Company, Drug Metabolism and Pharmacokinetics Section, Stine-Haskell Research Center, Newark, Delaware 19714, USA.
Aungst
B J
BJ
Eyermann
C J
CJ
Huang
S M
SM
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D018938:Caco-2 Cells / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000502:physiology*; D019808:Losartan; D008297:Male; D008698:Mesylates / Q000737:chemistry / Q000493:pharmacokinetics*; D000442:Octanols / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000493:pharmacokinetics*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; C103512:DuP 167; D007093:Imidazoles; D007211:Indoles; D008698:Mesylates; D000442:Octanols; D010456:Peptides, Cyclic; D011725:Pyridines; D013777:Tetrazoles; C085286:DMP 728; C061017:linopirdine; D019808:Losartan