Absorption of angiotensin II antagonists in Ussing chambers, Caco-2, perfused jejunum loop and in vivo: importance of drug ionisation in the in vitro prediction of in vivo absorption.

摘要: The aims of this study were (i) to compare the absorption three closely related inhibitors angiotensin II, RU60018, RU60079 and HR720, in various vitro vivo models, (ii) explain differences results assess importance drug ionisation predict absorption. Drug was investigated Ussing chambers, Caco-2 cell monolayers, perfused rat jejunum loops after oral, intraduodenal or intravenous administration. In analogues showed same site-related profile a common mechanism involving paracellular pathway. At pH 7.4 loop transport studies, compounds exhibited low comparable permeability values suggesting that similar level oral may be expected for all compounds. However, administration, only HR720 significantly absorbed. can explained by ionic distribution which indicated possessed significant amount uncharged species at close found upper part intestinal tract. Hence, it is intestine, favoured. This supported studies performed when apical medium lowered from 6.0, dramatic increase observed compared those other analogues. highlights usefulness different models screening demonstrates profiles must carefully considered avoid rejection promising