Torcetrapib
Torcetrapib shifts almost entirely into triglyceride-rich lipoproteins in hyperlipidemic human plasma (Pharm Res 2006)
Original title: The in vitro plasma distribution of a novel cholesteryl ester transfer protein inhibitor, torcetrapib, is influenced by differences in plasma lipid concentrations
Researchers measured how torcetrapib distributes across plasma lipoprotein fractions (triglyceride-rich lipoprotein [TRL], LDL, HDL, and lipoprotein-deficient plasma) after incubation in normolipidemic (total cholesterol 164 mg/dL, triglycerides 139 mg/dL) versus hyperlipidemic (total cholesterol 260 mg/dL, triglycerides 775 mg/dL) human plasma, using density gradient ultracentrifugation and GC-MS/MS. At torcetrapib concentrations of 250 and 500 ng/mL, the drug distributed evenly across the four fractions in normolipidemic plasma, but in hyperlipidemic plasma approximately 84% of torcetrapib was found in the TRL fraction, with the remaining 16% split evenly among the other three fractions. The authors conclude lipid profile affects the plasma distribution of torcetrapib, and the preferential shift into TRL under hyperlipidemia warrants further study of whether it affects the pharmacological activity of the drug in vivo.
Original abstract
Purpose: To determine the lipoprotein distribution of Torcetrapib in normolipidemic or hyperlipidemic human plasma and assess any changes in distribution due to lipid profile.
Methods: Torcetrapib was incubated with human plasma samples, and the distribution was measured across four fractions: triglyceride-rich lipoprotein (TRL), low-density lipoprotein, high-density lipoprotein, and lipoprotein-deficient plasma fraction. Two stocks of human plasma were used, one considered normolipidemic (total cholesterol concentration = 164 mg/dL, triglycerides concentration = 139 mg/dL, protein concentration = 912 mg/dL), the other hyperlipidemic (total cholesterol = 260 mg/dL, triglycerides = 775 mg/dL, protein = 917 mg/dL). The plasma samples were incubated with Torcetrapib at 37 degrees C, and the incubation was stopped with the addition of sodium bromide and cooling to 4 degrees C. The plasma samples were then separated by density gradient ultracentrifugation to their lipoprotein fractions. The resulting lipoprotein fractions and an aliquot of incubated plasma were analyzed by a validated gas chromatography/tandem mass spectrometry analytical method. The distribution of Torcetrapib was determined first with varying incubation times, then with several concentrations.
Results: At concentrations of 250 and 500 ng/mL, Torcetrapib distributed evenly across the four fractions in normolipidemic plasma. At the same concentrations in hyperlipidemic plasma, approximately 84% of Torcetrapib was found in the TRL fraction, with the remaining 16% evenly partitioned between the low-density lipoprotein, high-density lipoprotein, and lipoprotein-deficient plasma fractions.
Conclusions: The results suggest that lipid profile affects the distribution of Torcetrapib in hyperlipidemic human plasma lipoprotein fractions. The preferential distribution of Torcetrapib into the TRL fraction in hyperlipidemic plasma needs to be investigated to see if it will affect the pharmacological effect of Torcetrapib in vivo.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.