EXCRETION AND METABOLISM OF REMIKIREN, A POTENT ORALLY-ACTIVE INHIBITOR OF PRIMATE RENIN

1. Following intravenous administration of C-14-remikiren to the male rat, 78 % of the administered radioactivity was recovered in faeces, i ndicating high biliary elimination. Of the 25 +/- 0.1 % of the dose re covered in urine, the majority (16.5 % of dose) was intact drug. 2. Af ter oral administration to the male rat the urinary recovery was marke dly reduced (85 +/- 2.0 % of dose), and virtually all of the material was excreted as an inactive hydrolysis product. Intact drug was non-de tectable, suggesting extensive first-pass metabolism. 3. Perfusion of isolated rat liver confirmed high biliary elimination, coupled with ex tensive metabolism. Although intact remikiren was the major component in bile (20 % of the 'dose'), the majority of the radioactivity was re covered as a series of mono- and dihydroxylated metabolites. 4. When s creened against human renin, only one of the metabolites in bile and u rine (mono-hydroxylated in the t-butyl side chain, and synthesized as Ro 44-0444) showed comparable activity to remikiren. The remaining ten metabolites rested were at least one order of magnitude less active t han the parent drug. 5. In comparative in vitro studies Po 44-0444 was formed by rat, but not human or cynomolgus monkey, liver microsomes. The primate microsomes also produced more of the remaining mono- and d i-hydroxy products, suggesting that metabolites make little contributi on to the oral activity of remikiren which is observed in these specie s in vivo.