Metabolism and excretion of [14C]taranabant, a cannabinoid-1 inverse agonist, in humans.
Taranabant (N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5 mg/201 μCi [14C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (∼92%), with the majority of the dose (∼87%) excreted into faeces and a much smaller fraction (∼5%) into urine. Taranabant was absorbed rapidly, with C(max) of radioactivity attained at 1-2-h postdose. The parent compound and its monohydroxylated metabolite, M1, were the major radioactive components circulating in plasma and comprised ∼12-24% and 33-42%, respectively, of the plasma radioactivity for up to 48 h. A second monohydroxylated metabolite, designated as M1a, represented ∼10-12% of the radioactivity in the 2- and 8-h postdose plasma profiles. Metabolite profiles of the faeces samples consisted mainly of the (unabsorbed) parent compound and multiple diastereomeric carboxylic acid derivatives derived from oxidation of the geminal methyl group of the parent compound and of the hydroxylated metabolite/s. These data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route.
Karanam
Bindhu
B
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, NJ 07065, USA. bindhu_karanam@merck.com
Addy
Carol
C
Bateman
Thomas
T
Reddy
Vijay Bhasker
VB
Li
Susie
S
Dean
Dennis
D
Li
Hankun
H
Jones
Allen
A
Schenk
David
D
Zhang
Andy Shiqiang
AS
Braun
Matt
M
Freeman
Amanda
A
Flach
Stephen
S
Stoch
Aubrey
A
Chodakewitz
Jeff
J
Wagner
John A
JA
Kumar
Sanjeev
S
D000577:Amides / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes / Q000032:analysis; D054314:Drug Inverse Agonism; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D011725:Pyridines / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*
D000577:Amides; D002250:Carbon Radioisotopes; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide