Huang Juan, Guo Lan, Tan Ruixiang, Wei Meijin, Zhang Jing, Zhao Ya, Gong Lu, Huang Zhihai, Qiu Xiaohui
The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China.
Front Pharmacol. 2018 Jun 22;9:646. doi: 10.3389/fphar.2018.00646. eCollection 2018.
Emodin, a major active anthraquinone, frequently interacts with other drugs. As changes of efflux transporters on intestine are one of the essential reasons why the drugs interact with each other, a validated Ussing chamber technique was established to detect the interactions between emodin and efflux transporters, including P-glycoprotein (P-gp), multidrug-resistant associated protein 2 (MRP2), and multidrug-resistant associated protein 3 (MRP3). Digoxin, pravastatin, and teniposide were selected as the test substrates of P-gp, MRP2, and MRP3. Verapamil, MK571, and benzbromarone were their special inhibitors. The results showed that verapamil, MK571, and benzbromarone could increase digoxin, pravastatin, and teniposide absorption, and decrease their values, respectively. Verapamil (220 μM) could significantly increase emodin absorption at 9.25 μM. In the presence of MK571 (186 μM), the values of emodin from M-S were significantly increased and the efflux ratio decreased. With the treatment of emodin (185, 370, and 740 μM), digoxin absorption was significantly decreased while teniposide increased. These results indicated that emodin might be the substrate of P-gp and MRP2. Besides, it might be a P-gp inducer and MRP3 inhibitor on enterocyte, which are reported for the first time. These results will be helpful to explain the drug-drug interaction mechanisms between emodin and other drugs and provide basic data for clinical combination therapy.
大黄素是一种主要的活性蒽醌，常与其他药物相互作用。由于肠道中外排转运体的变化是药物相互作用的重要原因之一，因此建立了一种经过验证的Ussing chamber技术来检测大黄素与外排转运体之间的相互作用，这些外排转运体包括P-糖蛋白（P-gp）、多药耐药相关蛋白2（MRP2）和多药耐药相关蛋白3（MRP3）。地高辛、普伐他汀和替尼泊苷被选为P-gp、MRP2和MRP3的测试底物。维拉帕米、MK571和苯溴马隆是它们的特异性抑制剂。结果表明，维拉帕米、MK571和苯溴马隆可分别增加地高辛、普伐他汀和替尼泊苷的吸收，并降低它们的[具体数值]。维拉帕米（220 μM）可显著增加9.25 μM大黄素的吸收。在MK571（186 μM）存在的情况下，大黄素从黏膜到浆膜的[具体数值]显著增加，外排率降低。用大黄素（185、370和740 μM）处理后，地高辛的吸收显著降低，而替尼泊苷的吸收增加。这些结果表明，大黄素可能是P-gp和MRP2的底物。此外，它可能是肠上皮细胞上的P-gp诱导剂和MRP3抑制剂，这是首次报道。这些结果将有助于解释大黄素与其他药物之间的药物相互作用机制，并为临床联合治疗提供基础数据。
