The absorption of β-adrenoceptor antagonists in rat in-situ small intestine; the effect of lipophilicity

Abstract

Abstract The absorption of β-adrenoceptor antagonists in rat in-situ small intestine; the effect of lipophilicity Intestinal absorption characteristics of eleven β-adrenoceptor antagonists were measured by monitoring their disappearance from in-situ intestinal loops in the anaesthetized rat. All have basic pKa values of around 9.5 (with the exception of sotalol) but show a wide range of lipophilic character (octanol-water log P values from −0.79 to 3.65). The results show two types of absorption behaviour, indicating different mechanisms for ‘hydrophilic’ and ‘lipophilic’ β-adrenoceptor antagonists. The four most hydrophilic molecules (sotalol, atenolol, nadolol and practolol) show virtually identical absorption rate constants. Absorption is slow and relative rates in jejunum (mean pH 6.5) and ileum (mean pH 7.3) are not consistent with pH-partition (jejunum > ileum). The more lipophilic members of the series (pindolol, timolol, metoprolol, oxprenolol, alprenolol and propranolol) are all absorbed much more rapidly. Absorption rate constant rises rapidly with log P and the expected pH effects are seen (ileum > jejunum). Acebutolol shows anomalously slow absorption for its log P value.