Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans.
Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (approximately 2 microM equivalents of [(14)C]anacetrapib) was achieved approximately 4 h postdose. The parent compound was the major radioactive component (79-94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing <or=14% of the radioactivity in plasma or fecal samples. In vitro data indicated that anacetrapib is metabolized mainly by CYP3A4 to form M1, M2, and M3. Overall, these data, along with those from other preclinical and clinical studies, indicate that anacetrapib probably exhibits a low-to-moderate degree of oral absorption in humans and the absorbed fraction of the dose is eliminated largely via CYP3A4-catalyzed oxidative metabolism, followed by excretion of metabolites by the biliary-fecal route.
Kumar
Sanjeev
S
Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, New Jersey 07065, USA. sanjeev_kumar@merck.com
Tan
Eugene Y
EY
Hartmann
Georgy
G
Biddle
Zachary
Z
Bergman
Arthur J
AJ
Dru
James
J
Ho
Jonathan Z
JZ
Jones
Allen N
AN
Staskiewicz
Steve J
SJ
Braun
Matthew P
MP
Karanam
Bindhu
B
Dean
Dennis C
DC
Gendrano
Isaias Noel
IN
Graves
Mark W
MW
Wagner
John A
JA
Krishna
Rajesh
R
D000293:Adolescent; D000328:Adult; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D015394:Molecular Structure; D023303:Oxazolidinones / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D023303:Oxazolidinones; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C530884:anacetrapib