Increased Expression of Hepatic Organic Cation Transporter 1 and Hepatic Distribution of Metformin in High-fat Diet-induced Obese Mice

Although the effect of obesity on drug disposition remains an important issue for clinicians, little is known about the effects of obesity on organic cation transporter 1 (OCT1) expression and activity. Here, we show that hepatic OCT1 expression was higher in mice fed a high-fat (HF) diet for 19 wee...

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Bibliographic Details
Published in:DRUG METABOLISM AND PHARMACOKINETICS 2010-01, Vol.25 (4), p.392-397
Main Authors: Jang, Eun-Hee, Klm, Hyoung-Kwang, Park, Chang-Shin, Kang, Ju-Hee
Format: Article
Language:English
Subjects:
Animals
Dietary Fats - administration & dosage
drug distribution
Hep G2 Cells
hepatic transport
Humans
Hypoglycemic Agents - pharmacokinetics
insulin
Insulin - pharmacology
leptin
Leptin - pharmacology
Liver - metabolism
Male
metformin
Metformin - pharmacokinetics
Mice
Mice, Inbred C57BL
Mice, Obese
obesity
Obesity - metabolism
OCT
Octamer Transcription Factor-1 - genetics
RNA, Messenger - analysis
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Although the effect of obesity on drug disposition remains an important issue for clinicians, little is known about the effects of obesity on organic cation transporter 1 (OCT1) expression and activity. Here, we show that hepatic OCT1 expression was higher in mice fed a high-fat (HF) diet for 19 weeks compared with mice fed a control diet. Since HF diet-induced obese mice exhibited elevation of plasma proinflammatory cytokines, leptin, and insulin levels, we evaluated the effect of leptin, insulin, and tumor necrosis factor-alpha (TNF-α) on OCT1 mRNA expression in HepG2 cells. Both leptin and insulin significantly increased OCT1 mRNA expression in HepG2 cells, but TNF-α did not. This finding was consistent with in vivo results. Using the OCT1 substrate metformin, we further measured the extent of hepatic uptake of metformin in obese and lean mice using the ratio of hepatic concentration to plasma concentration of metformin at 1 h after administration. The hepatic uptake of metformin was significantly higher in mice fed a HF diet compared with lean mice. In conclusion, our results suggest, at least in part, that obesity might have an effect on the absorption or distribution pharmacokinetics of metformin through an increase in hepatic OCT1 expression.
ISSN:1347-4367
1880-0920
DOI:10.2133/dmpk.DMPK-10-NT-010