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Drug Metabolism and Disposition Fast Forward
First published on August 24, 2004; DOI: 10.1124/dmd.104.000604

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Received for publication May 14, 2004.
Revised August 20, 2004.
Accepted for publication August 20, 2004.

Metabolism and Disposition of Calcimimetic agent Cinacalcet HCl in Humans and Animal Models

Gondi N Kumar 1*, Christopher Sproul 1, Leszek Poppe 1, Sharon Turner 1, Mark Gohdes 2, Hesham Ghoborah 1, Desmond Padhi 1, Lorin Roskos 1

1 Amgen Inc. 2 Covance Laboratories Inc.

* Address correspondence to: E-mail: gkumar{at}amgen.com

Abstract

The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined following a single oral administration to mice, rats, monkeys and human volunteers. In all species examined, cinacalcet was well absorbed, with greater than 74% oral bioavailability of cinacalcet-derived radioactivity in monkeys and humans. In rats, cinacalcet-derived radioactivity was widely distributed into most tissues, with no marked gender-related differences. In all animal models examined, radioactivity was excreted rapidly via both hepato-biliary and urinary routes. In humans, radioactivity was cleared primarily via the urinary route (80%), with 17% excreted in the feces. Cinacalcet was not detected in the urine in humans. The primary routes of metabolism of cinacalcet were N-dealkylation leading to carboxylic acid derivatives (excreted in urine as glycine conjugates) and oxidation of naphthalene ring to form dihydrodiols (excreted in urine and bile as glucuronide conjugates). The plasma radioactivity in both animals and humans was primarily composed of carboxylic acid metabolites and dihydrodiol glucuronides, with <1% circulating radioactivity accounting for the unchanged cinacalcet. Overall, the circulating and excreted metabolite profile of cinacalcet in humans was qualitatively similar to that observed in preclinical animal models.


Key words: biliary excretion, drug disposition, drug distribution, human pharmacokinetics, metabolite indentification


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