Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers.
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 [(14)C]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 (C(max)) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC(0-infinity)), 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.
Waldmeier
Felix
F
Novartis Pharma AG, Basel, Switzerland. felix.waldmeier@novartis.com
Glaenzel
Ulrike
U
Wirz
Bernard
B
Oberer
Lukas
L
Schmid
Dietmar
D
Seiberling
Michael
M
Valencia
Jessica
J
Riviere
Gilles-Jacques
GJ
End
Peter
P
Vaidyanathan
Sujata
S
D000328:Adult; D000577:Amides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D019540:Area Under Curve; D001711:Biotransformation; D005243:Feces / Q000737:chemistry; D005650:Fumarates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D014018:Tissue Distribution; D014556:Urine / Q000737:chemistry; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren