Distribution of remikiren, a potent orally active inhibitor of human renin, in laboratory animals.

1. Whole-body autoradiography was used to compare the distribution of remikiren in the squirrel monkey, in which the compound is a potent inhibitor of renin, with the rat and the guinea-pig in which it is less active. 2. Following intravenous administration, drug-related material was rapidly and extensively taken up by the tissues of all three species. Consistent with rapid biliary elimination, high levels of radioactivity were found in the bile duct/gall bladder/intestinal contents. Of the remaining organs, the kidney consistently showed the highest concentrations of drug-related material. 3. Radio-hplc analysis of the kidney samples demonstrated that the majority of the retained material was present as intact remikiren, even at 24 h after administration. A similar degree of retention by the kidney was also found after oral dosing. 4. Uptake of remikiren by the kidney may act as a reservoir for the drug, resulting in the prolonged duration of pharmacological activity, which, despite the high plasma clearance of the drug, has previously been observed in primates.

The contribution of intestinal secretion to the dose-dependent absorption of celiprolol.

The contribution of the intestine to the nonlinear absorption of celiprolol in the rat was studied. After intravenous administration of 14C-celiprolol to bile duct-cannulated rats, approximately 9% of the dose was found to be associated with intestinal tissue and its contents. Microhistoautoradiography of frozen intestinal sections showed a time-dependent secretion of celiprolol from the blood into the lumen of the rat intestine. Propranolol, a lipophilic beta-blocker, was also found to be secreted into the intestine in vivo and transported in epithelial cells in both a temperature- and a pH-dependent manner, although to a lesser extent than celiprolol. Consistent with the observations in rats, transport of celiprolol from the basal-lateral to the apical side was found to dominate apical-to-basal transport using human Caco-2 cell monolayers. Additionally, using isolated rat small intestinal epithelial cells, celiprolol was found also to have a time- and temperature-dependent uptake, suggesting the involvement of a carrier-mediated system in its uptake. The uptake was inhibited by 2 mM celiprolol and propranolol and was also found to be pH dependent. Saturation of the carrier-mediated secretion of celiprolol in the intestine may result in enhanced absorption of celiprolol at high doses and account for its observed nonlinear absorption.