Abstract
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.
Footnotes
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This study was supported by Novartis Pharma AG, Basel, Switzerland.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.013797.
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ABBREVIATIONS: P450, cytochrome P450; HPLC, high performance liquid chromatography; AMS, accelerator mass spectrometry; AUC0–∞,area under the concentration-time curve from time zero to infinity; AUC0–t, area under the concentration-time curve from time zero to t (last measured time point above LOQ); CL/F, apparent plasma clearance; LOQ, limit of quantification; LSC, liquid scintillation counting; MS, mass spectrometry; MS/MS, tandem mass spectrometry; ADME, absorption, distribution, metabolism, and excretion; t½, elimination half-life; tmax, time to maximum concentration.
- Received November 10, 2006.
- Accepted May 16, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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