TY - JOUR T1 - Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1418 LP - 1428 DO - 10.1124/dmd.106.013797 VL - 35 IS - 8 AU - Felix Waldmeier AU - Ulrike Glaenzel AU - Bernard Wirz AU - Lukas Oberer AU - Dietmar Schmid AU - Michael Seiberling AU - Jessica Valencia AU - Gilles-Jacques Riviere AU - Peter End AU - Sujata Vaidyanathan Y1 - 2007/08/01 UR - http://dmd.aspetjournals.org/content/35/8/1418.abstract N2 - Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [14C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose. Peak plasma levels of aliskiren (Cmax) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC0–∞), and indicating very low exposure to metabolites. Terminal half-lives for radioactivity and aliskiren in plasma were 49 h and 44 h, respectively. Dose recovery over 168 h was nearly complete (91.5% of dose); excretion occurred almost completely via the fecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in feces in unchanged form. Based on results from this and from previous studies, the absorbed fraction of aliskiren can be estimated to approximately 5% of dose. The absorbed dose was partly eliminated unchanged via the hepatobiliary route. Oxidized metabolites in excreta accounted for at least 1.3% of the radioactive dose. The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative. The American Society for Pharmacology and Experimental Therapeutics ER -