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Received for publication November 15, 2006.
Revised May 14, 2007.
Accepted for publication May 16, 2007.
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, non-peptide 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 faeces collections were made for 168 h post-dose. Peak plasma levels of aliskiren (Cmax) were achieved between 2 and 5 h post-dose. 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 faecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in faeces 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.
Key words:
absorption, biliary excretion, distribution, drug disposition, metabolite identification
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