Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans.
OBJECTIVE
Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins.


RESULTS
Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production.


CONCLUSIONS
These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.
Millar
John S
JS
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. jsmillar@mail.med.upenn.edu
Brousseau
Margaret E
ME
Diffenderfer
Margaret R
MR
Barrett
P Hugh R
PH
Welty
Francine K
FK
Faruqi
Aisha
A
Wolfe
Megan L
ML
Nartsupha
Chorthip
C
Digenio
Andres G
AG
Mancuso
James P
JP
Dolnikowski
Gregory G
GG
Schaefer
Ernst J
EJ
Rader
Daniel J
DJ
D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D000069059:Atorvastatin; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D018592:Cross-Over Studies; D004357:Drug Synergism; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D008079:Lipoproteins, VLDL / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D008875:Middle Aged; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D016037:Single-Blind Method
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D008074:Lipoproteins; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin