Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism.
Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor torcetrapib on VLDL apolipoprotein E (apoE) metabolism. Subjects, pretreated with atorvastatin (n = 9) or untreated (n = 10), received placebo followed by torcetrapib (4 weeks each). After each treatment, subjects underwent a primed-constant infusion of D(3)-leucine to determine the VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib alone reduced the VLDL apoE pool size (PS) (-28%) by increasing the VLDL apoE FCR (77%) and leaving the VLDL apoE PR unchanged. In subjects pretreated with atorvastatin, torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Used alone, torcetrapib reduces the VLDL apoE PS by increasing the apoE FCR while leaving the VLDL apoE content unchanged. In contrast, torcetrapib added to atorvastatin treatment increases both the VLDL apoE FCR and PR, leaving the VLDL apoE PS unchanged. Adding torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL.
Millar
John S
JS
Department of Pharmacology, 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
Cohn
Jeffrey S
JS
Wilson
Aisha
A
Wolfe
Megan L
ML
Nartsupha
Chorthip
C
Schaefer
Peter M
PM
Digenio
Andres G
AG
Mancuso
James P
JP
Dolnikowski
Gregory G
GG
Schaefer
Ernst J
EJ
Rader
Daniel J
DJ
D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001057:Apolipoproteins E / Q000096:biosynthesis / Q000378:metabolism*; D000069059:Atorvastatin; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D007700:Kinetics; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D016037:Single-Blind Method
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D011804:Quinolines; C483909:torcetrapib; D000069059:Atorvastatin