Metabolism and disposition of calcimimetic agent cinacalcet HCl in humans and animal models.
The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after 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 hepatobiliary 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.
Kumar
Gondi N
GN
Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA, USA. gkumar@amgen.com
Sproul
Christopher
C
Poppe
Leszek
L
Turner
Sharon
S
Gohdes
Mark
M
Ghoborah
Hesham
H
Padhi
Desmond
D
Roskos
Lorin
L
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002853:Chromatography, Liquid; D000069449:Cinacalcet; D005243:Feces / Q000737:chemistry; D006801:Humans; D007553:Isotope Labeling; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000493:pharmacokinetics* / Q000652:urine; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution
D009281:Naphthalenes; D000069449:Cinacalcet