Intestinal absorption of a .BETA.-adrenergic blocking agent nadolol. III Nuclear magnetic resonance spectroscopic study on nadolol-sodium cholate micellar complex and intestinal absorption of nadolol derivatives in rats.

Abstract

The stable micellar complex formation between nadolol and sodium cholate was studied. The proton nuclear magnetic resonance spectroscopic study showed that the signals of protons in the hydrophobic site of cholic acid, i.e., the methine signals of C-7 and C-12, and the methyl signals of C-18 and C-19. exhibited rather larger shifts than those of the other protons. The longitudinal relaxation times of the aromatic ring protons (C-4, C-6, C-7 and C-8) of nadolol were shortened by about 10% in the presence of sodium cholate, indicating that the aromatic ring protons were more immobilized upon complex formation. These results suggest that the hydrophobic protons of sodium cholate and nadolol interact with each other, and complex formation with the hydrophobic protons inside and the hydrohilic protons outside may occur in aqueous solution. The intestinal absorption of four nadolol derivatives was examined by the in situ ligated loop method in rat jejunum in the presence of sodium cholate. The absorption of the trans-2, 3-diol isomer was inhibited as effectively as that of nadolol. The absorption of the 2-and 3-monohydroxy derivatives and cis-2, 3-dimethoxy derivative was inhibited by sodium cholate at 1 h after dosing, but no inhibition was observed at 4 h. This absorption behavior of nadolol derivatives was well correlated with the apparent dissociation constants of their micellar complexes with sodium cholate. It is concluded that the stability of the complexes of β-adrenergic blocking agents with sodium cholate depends upon the steric features of both hydrophobic and hydrophilic parts of the drug molecules. The hydrophilic cis-2, 3-diol moiety of nadolol plays an important role in stabilizing the micellar complex with sodium cholate.