Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland.
Department of Clinical Pharmacology, University Medicine of Greifswald, Greifswald, Germany.
Clin Pharmacol Ther. 2019 May;105(5):1204-1212. doi: 10.1002/cpt.1301. Epub 2019 Jan 11.
Bioavailability of orally administered drugs is partly determined by function of drug transporters in the liver and intestine. Therefore, we explored adenosine triphosphate-binding cassette (ABC) and solute carriers family transporters expression (quantitative polymerase chain reaction) and protein abundance (liquid chromatography tandem mass spectrometry (LC-MS/MS)) in human liver and duodenum, jejunum, ileum, and colon in paired tissue specimens from nine organ donors. The transporter proteins were detected in the liver (permeability-glycoprotein (P-gp), multidrug resistance protein (MRP)2, MRP3, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic cation transporter (OCT)1, OCT3, organic anion transporter 2, Na+-taurocholate cotransporting polypeptide, monocarboxylate transporter (MCT)1, and multidrug and toxin extrusion 1) and the intestine (P-gp, multidrug-resistance protein (MRP)2, MRP3, MRP4, BCRP, OATP2B1, OCT1, apical sodium-bile acid transporter (only ileum), MCT1, and peptide transporter (PEPT1)). Significantly higher hepatic gene expression and protein abundance of ABCC2/MRP2, SLC22A1/OCT1, and SLCO2B1/OATP2B1 were found, as compared to all intestinal segments. No correlations between hepatic and small intestinal protein levels were observed. These observations provide a description of drug transporters distribution without the impact of interindividual variability bias and may help in construction of superior physiologically based pharmacokinetic and humanized animal models.
口服药物的生物利用度部分取决于肝脏和肠道中药物转运体的功能。因此，我们在 9 位器官捐献者的配对组织标本中探索了人肝和十二指肠、空肠、回肠和结肠中三磷酸腺苷结合盒（ABC）和溶质载体家族转运蛋白的表达（定量聚合酶链反应）和蛋白丰度（液相色谱串联质谱法（LC-MS/MS））。在肝脏（P-糖蛋白（P-gp）、多药耐药蛋白（MRP）2、MRP3、乳腺癌耐药蛋白（BCRP）、有机阴离子转运多肽（OATP）1B1、OATP1B3、OATP2B1、有机阳离子转运体（OCT）1、OCT3、有机阴离子转运体 2、牛磺胆酸钠共转运蛋白、单羧酸转运体（MCT）1 和多药和毒素外排 1）和肠道（P-gp、多药耐药蛋白（MRP）2、MRP3、MRP4、BCRP、OATP2B1、OCT1、顶端钠-胆酸转运体（仅回肠）、MCT1 和肽转运体（PEPT1））中检测到转运蛋白。与所有肠段相比，发现 ABCC2/MRP2、SLC22A1/OCT1 和 SLCO2B1/OATP2B1 的肝基因表达和蛋白丰度显著更高。未观察到肝和小肠蛋白水平之间的相关性。这些观察结果提供了一种没有个体间变异性偏差影响的药物转运体分布描述，可能有助于构建更好的基于生理学的药代动力学和人性化动物模型。
