Oswald Stefan, Giessmann Thomas, Luetjohann Dieter, Wegner Danilo, Rosskopf Dieter, Weitschies Werner, Siegmund Werner
Department of Clinical Pharmacology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany.
Clin Pharmacol Ther. 2006 Nov;80(5):477-85. doi: 10.1016/j.clpt.2006.07.006.
The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs).
The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection.
After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0+/-4.20 ng/mL versus 4.67+/-2.72 ng/mL, P=.017, and 282+/-73.8 ng/mL versus 107+/-35.3 ng/mL, P=.012, respectively). The area under the curve of ezetimibe was not affected (102+/-37.6 ng.h/mL versus 140+/-86.3 ng.h/mL, P=not significant), whereas that of the glucuronide was markedly increased (2150+/-687 ng.h/mL versus 1030+/-373 ng.h/mL, P=.012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6+/-2.2 mg versus 10.4+/-1.8 mg, P=.036), whereas renal excretion of the glucuronide was strongly elevated (4.8+/-1.9 mg versus 2.0+/-1.2 mg, P=.049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration.
Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2.
依折麦布的分布及降胆固醇作用与持久的肠肝循环相关，该循环由依折麦布及其葡萄糖醛酸苷经肠道P-糖蛋白（P-gp，ABCB1）和多药耐药相关蛋白2（MRP2，ABCC2）分泌至肠腔启动。肝脏摄取和分泌可能有助于再循环。为更深入了解肠道和肝脏过程，在利福平（国际非专利药品名称，利福平）存在的情况下研究了依折麦布的分布，利福平是P-gp、MRP2和肝脏有机阴离子（摄取）转运多肽（OATP，SLCO）的调节剂。
在一项对8名具有SLCO1B1 *1a/*1a基因型的健康受试者进行的交叉研究中，测量了单独口服依折麦布（20 mg）以及与利福平（口服600 mg）合用时依折麦布的分布情况。采用液相色谱和气相色谱 - 质谱检测法定量血清、尿液和粪便中依折麦布及其葡萄糖醛酸苷的浓度，以及血清中的胆固醇、羊毛甾醇和植物甾醇菜油甾醇和谷甾醇。
服用利福平后，依折麦布及其葡萄糖醛酸苷的血清最大浓度显著升高（分别为12.0±4.20 ng/mL对4.67±2.72 ng/mL，P = 0.017；282±73.8 ng/mL对107±35.3 ng/mL，P = 0.012）。依折麦布的曲线下面积未受影响（102±37.6 ng·h/mL对140±86.3 ng·h/mL，P无显著性差异），而葡萄糖醛酸苷的曲线下面积显著增加（2150±687 ng·h/mL对1030±373 ng·h/mL，P = 0.012）。肾脏清除率保持不变。合用后依折麦布的粪便排泄显著减少（7.6±2.2 mg对10.4±1.8 mg，P = 0.036），而葡萄糖醛酸苷的肾脏排泄显著增加（4.8±1.9 mg对2.0±1.2 mg，P = 0.049）。合用利福平显著缩短了依折麦布显著降胆固醇作用的起效时间。
合用利福平增加了依折麦布的血清最大浓度，但减少了其肠肝循环，很可能是通过抑制依折麦布及其葡萄糖醛酸苷经P-gp和MRP2的分泌实现的。
