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


CONCLUSIONS
The antidiabetic effect of metformin may be diminished in diabetic patients with EE cholestasis, due to impaired hepatic uptake of the drug via OCT1.
Jin
Hyo-Eon
HE
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.
Hong
Soon-Sun
SS
Choi
Min-Koo
MK
Maeng
Han-Joo
HJ
Kim
Dae-Duk
DD
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D015153:Blotting, Western; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000096:biosynthesis*; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D015536:Down-Regulation; D004997:Ethinyl Estradiol / Q000009:adverse effects*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008687:Metformin / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D014018:Tissue Distribution
D001798:Blood Proteins; D050482:Catecholamine Plasma Membrane Transport Proteins; D007004:Hypoglycemic Agents; C493212:Slc22a1 protein, rat; D004997:Ethinyl Estradiol; D008687:Metformin; D005947:Glucose