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Research ArticleArticle

Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers

Felix Waldmeier, Ulrike Glaenzel, Bernard Wirz, Lukas Oberer, Dietmar Schmid, Michael Seiberling, Jessica Valencia, Gilles-Jacques Riviere, Peter End and Sujata Vaidyanathan
Drug Metabolism and Disposition August 2007, 35 (8) 1418-1428; DOI: https://doi.org/10.1124/dmd.106.013797
Felix Waldmeier
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Ulrike Glaenzel
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Bernard Wirz
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Lukas Oberer
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Dietmar Schmid
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Michael Seiberling
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Jessica Valencia
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Gilles-Jacques Riviere
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Peter End
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Sujata Vaidyanathan
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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

  • This study was supported by Novartis Pharma AG, Basel, Switzerland.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.013797.

  • 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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Drug Metabolism and Disposition: 35 (8)
Drug Metabolism and Disposition
Vol. 35, Issue 8
1 Aug 2007
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Research ArticleArticle

Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers

Felix Waldmeier, Ulrike Glaenzel, Bernard Wirz, Lukas Oberer, Dietmar Schmid, Michael Seiberling, Jessica Valencia, Gilles-Jacques Riviere, Peter End and Sujata Vaidyanathan
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1418-1428; DOI: https://doi.org/10.1124/dmd.106.013797

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Research ArticleArticle

Absorption, Distribution, Metabolism, and Elimination of the Direct Renin Inhibitor Aliskiren in Healthy Volunteers

Felix Waldmeier, Ulrike Glaenzel, Bernard Wirz, Lukas Oberer, Dietmar Schmid, Michael Seiberling, Jessica Valencia, Gilles-Jacques Riviere, Peter End and Sujata Vaidyanathan
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1418-1428; DOI: https://doi.org/10.1124/dmd.106.013797
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