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, indicating high biliary elimination. Of the 25 +/- 0.1 % of the dose recovered in urine, the majority (16.5 % of dose) was intact drug. 2. After oral administration to the male rat the urinary recovery was markedly reduced (85 +/- 2.0 % of dose), and virtually all of the material was excreted as an inactive hydrolysis product. Intact drug was non-detectable, suggesting extensive first-pass metabolism. 3. Perfusion of isolated rat liver confirmed high biliary elimination, coupled with extensive metabolism. Although intact remikiren was the major component in bile (20 % of the 'dose'), the majority of the radioactivity was recovered as a series of mono- and dihydroxylated metabolites. 4. When screened against human renin, only one of the metabolites in bile and urine (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 than 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 di-hydroxy products, suggesting that metabolites make little contribution to the oral activity of remikiren which is observed in these species in vivo.