Jin Hyo-Eon, Hong Soon-Sun, Choi Min-Koo, Maeng Han-Joo, Kim Dae-Duk, Chung Suk-Jae, Shim Chang-Koo
National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul, 151-742, Republic of Korea.
Pharm Res. 2009 Mar;26(3):549-59. doi: 10.1007/s11095-008-9770-5. Epub 2008 Nov 11.
To investigate the effect of 17alpha-ethynylestradiol (EE)-induced cholestasis on the expression of organic cation transporters (Octs) in the liver and kidney, as well as the pharmacokinetics and pharmacodynamics of metformin in rats.
Octs mRNA and protein expression were determined. The pharmacokinetics and tissue uptake clearance of metformin were determined following iv administration (5 mg/kg). Uptake of metformin, glucagon-mediated glucose production, and AMP-activated protein kinase (AMPK) activation were measured in isolated hepatocytes. The effect of metformin (30 mg/kg) on blood glucose levels was tested using the iv glucose tolerance test (IVGTT).
The mRNAs of hepatic Oct1, renal Oct1, and Oct2 were decreased by 71.1%, 37.6%, and 94.5%, respectively, by EE cholestasis. The hepatic Oct1 and renal Oct2 proteins were decreased by 30.6% and 60.2%, respectively. The systemic and renal clearance of metformin were decreased. The in vitro hepatocyte uptake of metformin was decreased by 86.4% for V (max). Suppression of glucagon-stimulated glucose production and stimulation of AMPK activation in hepatocytes by metformin were diminished. In addition, metformin did not demonstrate a glucose-lowering effect during IVGTT in EE cholestasis.
The antidiabetic effect of metformin may be diminished in diabetic patients with EE cholestasis, due to impaired hepatic uptake of the drug via OCT1.
研究17α-乙炔雌二醇（EE）诱导的胆汁淤积对大鼠肝脏和肾脏中有机阳离子转运体（Octs）表达的影响，以及二甲双胍在大鼠体内的药代动力学和药效学。
测定Octs mRNA和蛋白表达。静脉注射（5 mg/kg）后测定二甲双胍的药代动力学和组织摄取清除率。在分离的肝细胞中测量二甲双胍的摄取、胰高血糖素介导的葡萄糖生成以及AMP激活的蛋白激酶（AMPK）激活。使用静脉葡萄糖耐量试验（IVGTT）测试二甲双胍（30 mg/kg）对血糖水平的影响。
EE胆汁淤积使肝脏Oct1、肾脏Oct1和Oct2的mRNA分别降低了71.1%、37.6%和94.5%。肝脏Oct1和肾脏Oct2蛋白分别降低了30.6%和60.2%。二甲双胍的全身清除率和肾脏清除率降低。体外肝细胞对二甲双胍的摄取V（max）降低了86.4%。二甲双胍对肝细胞中胰高血糖素刺激的葡萄糖生成的抑制作用和对AMPK激活的刺激作用减弱。此外，在EE胆汁淤积的IVGTT期间，二甲双胍未表现出降糖作用。
在患有EE胆汁淤积的糖尿病患者中，由于药物通过OCT1的肝脏摄取受损，二甲双胍的抗糖尿病作用可能减弱。
