Anacetrapib Alters Triglyceride Trafficking And Clearance In Rhesus Macaques: Interrogating The Mechanism Behind V/Ldl-Cholesterol Reduction

Cholesterol Ester Transfer Protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between HDL particles and apoB containing lipoproteins. Assessment of CETP activity has been mainly based upon in vitro transfer assays and, therefore, may not reflect the activity of CETP mediated exchange in vivo . Novel isotope tracer methods were developed to study the transfer of lipids in vivo . We used these techniques to systematically study lipid fluxes in lipoprotein particles from fed and fasted rhesus macaques before and after 10 days of treatment with the CETPi , anacetrapib. In two separate studies, dual isotopes of oleic acid, [ 2 H 11 ] p.o. in heavy cream and [ 13 C 18 ]i.v., were administered before and after treatment with anacetrapib 150 mg/kg Q.D.. Plasma samples, collected at eight times postprandially and at 24 h, were analyzed for total cholesterol and TG using biochemical methods, and lipoprotein fractions were analyzed for isotope labeled lipids using liquid chromatography and mass spectrometry. Treatment with anacetrapib increased total plasma cholesterol by >70%, and HDL cholesterol by >110%. A >90% (p 85% (p