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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Anticholesteremic Agents, Cholesterol Ester Transfer Proteins, Humans, In Vitro Techniques, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Protein Binding, Quinolines, Triglycerides.
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Is the in vitro plasma distribution of a novel cholesteryl ester transfer protein inhibitor , torcetrapib , influenced by differences in plasma lipid concentrations? Context: To determine the lipoprotein distribution of Torcetrapib in normolipidemic or hyperlipidemic human plasma and assess any changes in distribution due to lipid profile. 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. 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.
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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. Final Decision: yes