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Reduced antidiabetic effect of metformin and down-regulation of hepatic Oct1 in rats with ethynylestradiol-induced cholestasis.

Authors: Jin, HE  Hong, SS  Choi, MK  Maeng, HJ  Kim, DD  Chung, SJ  Shim, CK 
Citation: Jin HE, etal., Pharm Res. 2009 Mar;26(3):549-59. doi: 10.1007/s11095-008-9770-5. Epub 2008 Nov 11.
Pubmed: (View Article at PubMed) PMID:19002567
DOI: Full-text: DOI:10.1007/s11095-008-9770-5

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: The antidiabetic effect of metformin may be diminished in diabetic patients with EE cholestasis, due to impaired hepatic uptake of the drug via OCT1.


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RGD Object Information
RGD ID: 7243885
Created: 2013-05-20
Species: All species
Last Modified: 2013-05-20
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.