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.
Richter
W F
WF
Pharma Division, F. Hoffmann-La Roche AG, Basel, Switzerland.
Whitby
B R
BR
Chou
R C
RC
D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D002250:Carbon Radioisotopes; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008297:Male; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D012453:Saimiri; D014018:Tissue Distribution; D000092502:Renin Inhibitors
D002250:Carbon Radioisotopes; D007093:Imidazoles; D011480:Protease Inhibitors; D000092502:Renin Inhibitors; C065581:remikiren