Oswald Stefan, Haenisch Sierk, Fricke Christiane, Sudhop Thomas, Remmler Cornelia, Giessmann Thomas, Jedlitschky Gabriele, Adam Ulrike, Dazert Eike, Warzok Rolf, Wacke Wolfram, Cascorbi Ingolf, Kroemer Heyo K, Weitschies Werner, von Bergmann Klaus, Siegmund Werner
Department of Clinical Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Greifswald, Germany.
Clin Pharmacol Ther. 2006 Mar;79(3):206-17. doi: 10.1016/j.clpt.2005.11.004. Epub 2006 Feb 7.
Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate-glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin).
Serum concentrations of ezetimibe, as well as its glucuronide, and the plant sterols campesterol and sitosterol (surrogate for cholesterol absorption) were studied in 12 healthy subjects before and after rifampin comedication. In parallel, duodenal expression of UGT1A1, P-gp, MRP2, and NPC1L1 was quantified by use of real-time reverse transcriptase-polymerase chain reaction and quantitative immunohistochemical evaluation. The affinity of ezetimibe and its glucuronide to P-gp and MRP2 was assessed in P-gp- overexpressing Madin-Darby canine kidney II cells and P-gp-containing or MRP2-containing inside-out vesicles.
Up-regulation of intestinal P-gp, MRP2, and UGT1A1 (but not of NPC1L1) by rifampin was associated with markedly decreased areas under the curve of ezetimibe and its glucuronide (116 +/- 78.1 ng.h/mL versus 49.9 +/- 31.0 ng.h/mL and 635 +/- 302 ng.h/mL versus 225 +/- 86.4 ng.h/mL, respectively; both P = .002) and increased intestinal clearances (2400 +/- 1560 mL/min versus 5500 +/- 4610 mL/min [P = .003] and 76.6 +/- 113 mL/min versus 316 +/- 457 mL/min [P = .010], respectively) and nearly abolished sterol-lowering effects. Intestinal expression of UGT1A1, ABCB1, and ABCC2 was inversely correlated with the effects of ezetimibe on plant sterol serum concentrations. Parallel in vitro studies confirmed that ezetimibe glucuronide is a high-affinity substrate of MRP2 and has a low affinity to P-gp whereas ezetimibe interacts with P-gp and MRP2.
The disposition and sterol-lowering effects of ezetimibe are modified by metabolic degradation of the drug via intestinal UGT1A1 and either intestinal or hepatic secretion (or both) via P-gp and MRP2.
依折麦布是胆固醇摄取转运蛋白尼曼-匹克C1样蛋白（NPC1L1）的抑制剂。目标浓度会受到肠道尿苷二磷酸葡萄糖醛酸转移酶（UGTs）以及外排转运蛋白P-糖蛋白（P-gp，ABCB1）和多药耐药相关蛋白2（MRP2，ABCC2）的影响。本研究评估了这些因素在利福平（国际非专利药品名称，利福平）诱导UGT1A1、P-gp和MRP2前后对依折麦布的处置及降胆固醇作用的贡献。
在12名健康受试者中，研究了利福平联合用药前后依折麦布及其葡萄糖醛酸苷的血清浓度，以及植物甾醇菜油甾醇和谷甾醇（胆固醇吸收的替代指标）。同时，通过实时逆转录聚合酶链反应和定量免疫组化评估对UGT1A1、P-gp、MRP2和NPC1L1的十二指肠表达进行定量。在过表达P-gp的Madin-Darby犬肾II细胞以及含P-gp或含MRP2的内翻囊泡中评估依折麦布及其葡萄糖醛酸苷对P-gp和MRP2的亲和力。
利福平使肠道P-gp、MRP2和UGT1A1（而非NPC1L1）上调，这与依折麦布及其葡萄糖醛酸苷的曲线下面积显著降低相关（分别为116±78.1 ng·h/mL对49.9±31.0 ng·h/mL以及635±302 ng·h/mL对225±86.4 ng·h/mL；P均=0.002），且肠道清除率增加（分别为2400±1560 mL/min对5500±4610 mL/min [P = 0.003]以及76.6±113 mL/min对316±457 mL/min [P = 0.010]），降甾醇作用几乎消失。UGT1A1、ABCB1和ABCC2的肠道表达与依折麦布对植物甾醇血清浓度的影响呈负相关。平行的体外研究证实，依折麦布葡萄糖醛酸苷是MRP2的高亲和力底物，对P-gp亲和力低，而依折麦布与P-gp和MRP2相互作用。
依折麦布的处置及降甾醇作用通过药物经肠道UGT1A1的代谢降解以及经P-gp和MRP2的肠道或肝脏分泌（或两者兼有）而改变。
