RGD Reference Report - Reduced antidiabetic effect of metformin and down-regulation of hepatic Oct1 in rats with ethynylestradiol-induced cholestasis. - Rat Genome Database

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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.
RGD ID: 7243885
Pubmed: PMID:19002567   (View Abstract at PubMed)
DOI: DOI:10.1007/s11095-008-9770-5   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SLC22A1Humanintrahepatic cholestasis  ISOSlc22a1 (Rattus norvegicus)mRNA and protein:decreased expression:liverRGD 
SLC22A2Humanintrahepatic cholestasis  ISOSlc22a2 (Rattus norvegicus)mRNA and protein:decreased expression:kidneyRGD 
Slc22a1Ratintrahepatic cholestasis  IEP mRNA and protein:decreased expression:liverRGD 
Slc22a1Mouseintrahepatic cholestasis  ISOSlc22a1 (Rattus norvegicus)mRNA and protein:decreased expression:liverRGD 
Slc22a2Ratintrahepatic cholestasis  IEP mRNA and protein:decreased expression:kidneyRGD 
Slc22a2Mouseintrahepatic cholestasis  ISOSlc22a2 (Rattus norvegicus)mRNA and protein:decreased expression:kidneyRGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc22a1  (solute carrier family 22 member 1)
Slc22a2  (solute carrier family 22 member 2)

Genes (Mus musculus)
Slc22a1  (solute carrier family 22 (organic cation transporter), member 1)
Slc22a2  (solute carrier family 22 (organic cation transporter), member 2)

Genes (Homo sapiens)
SLC22A1  (solute carrier family 22 member 1)
SLC22A2  (solute carrier family 22 member 2)


Additional Information