Analysis of “On/Off” Kinetics of a CETP Inhibitor Using a Mechanistic Model of Lipoprotein Metabolism and Kinetics
作者： J Lu , Y Cleary , C Maugeais , CI Kiu Weber , NA Mazer
DOI: 10.1002/PSP4.27
关键词: Endocrinology 、 Lipoprotein metabolism 、 Chemistry 、 Pharmacokinetics 、 Calibration and validation 、 Bioinformatics 、 Reverse cholesterol transport 、 Kinetics 、 Apolipoprotein B 、 Oral administration 、 Internal medicine 、 CETP inhibitor
摘要: RG7232 is a potent inhibitor of cholesteryl-ester transfer protein (CETP). Daily oral administration produces dose- and time-dependent increase in high-density lipoprotein-cholesterol (HDL-C) apolipoproteinA-I (ApoA-I) levels corresponding decrease low-density (LDL-C) apolipoproteinB (ApoB) levels. Due to its short plasma half-life (∼3 hours), transiently inhibits CETP activity during each dosing interval ("on/off" kinetics), as reflected by the temporal effects on HDL-C LDL-C. The influence lipid-poor ApoA-I (i.e., pre-β 1) reverse cholesterol transport rates unclear. To investigate this, published model lipoprotein metabolism kinetics was combined with pharmacokinetic RG7232. After calibration validation model, effect 1 simulated. A dose-dependent oscillation 1, driven "on/off" observed. possible implications these findings are discussed.
sci-hub.se 参考文章(35)
Karim Wahba, Ananth Kadambi, Arthur Lo, Lyn M Powell, Abstract 9560: Clinical Trial Simulations of Dyslipidemic Patients in a Mechanistic Model of Cardiovascular Disease Predict Little Impact on CHD Events by CETP Inhibitors Circulation. ,vol. 124, ,(2011)
Ronald Gieschke, Daniel Serafin, Development of Innovative Drugs via Modeling with MATLAB : A Practical Guide ,(2013)
Rachel H. Mackey, Philip Greenland, David C. Goff, Donald Lloyd-Jones, Christopher T. Sibley, Samia Mora, High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). Journal of the American College of Cardiology. ,vol. 60, pp. 508- 516 ,(2012) , 10.1016/J.JACC.2012.03.060
M. Hersberger, A. von Eckardstein, Modulation of High-Density Lipoprotein Cholesterol Metabolism and Reverse Cholesterol Transport Handbook of experimental pharmacology. ,vol. 170, pp. 537- 561 ,(2005) , 10.1007/3-540-27661-0_20
D.A. Chappell, G.L. Fry, M.A. Waknitz, J.J. Berns, Ligand size as a determinant for catabolism by the low density lipoprotein (LDL) receptor pathway. A lattice model for LDL binding. Journal of Biological Chemistry. ,vol. 266, pp. 19296- 19302 ,(1991) , 10.1016/S0021-9258(18)54997-8
F Nigon, P Lesnik, M Rouis, MJ Chapman, Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor Journal of Lipid Research. ,vol. 32, pp. 1741- 1753 ,(1991) , 10.1016/S0022-2275(20)41629-3
Elias J. Jeyarajah, William C. Cromwell, James D. Otvos, Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clinics in Laboratory Medicine. ,vol. 26, pp. 847- 870 ,(2006) , 10.1016/J.CLL.2006.07.006
Robert S. Rosenson, H. Bryan Brewer, W. Sean Davidson, Zahi A. Fayad, Valentin Fuster, James Goldstein, Marc Hellerstein, Xian-Cheng Jiang, Michael C. Phillips, Daniel J. Rader, Alan T. Remaley, George H. Rothblat, Alan R. Tall, Laurent Yvan-Charvet, Cholesterol Efflux and Atheroprotection Advancing the Concept of Reverse Cholesterol Transport Circulation. ,vol. 125, pp. 1905- 1919 ,(2012) , 10.1161/CIRCULATIONAHA.111.066589
Wenrui Hao, Avner Friedman, The LDL-HDL Profile Determines the Risk of Atherosclerosis: A Mathematical Model PLoS ONE. ,vol. 9, pp. e90497- ,(2014) , 10.1371/JOURNAL.PONE.0090497
Bronwyn A. Kingwell, M. John Chapman, Anatol Kontush, Norman E. Miller, HDL-targeted therapies: progress, failures and future Nature Reviews Drug Discovery. ,vol. 13, pp. 445- 464 ,(2014) , 10.1038/NRD4279