Altered hepatic distribution of metformin, a substrate of organic cation transporter 1 (OCT1) in obese mice; Influence of insulin and leptin

초록

Although the effect of obesity on the drug-metabolizing enzymes or drug transporters remains an important issue for clinician, little is known about the effects of obesity on organic cation transporter 1 (OCT1) expression and activity. Metformin, a euglycemic anti-diabetic drug is a substrate of OCT1 and one of the major targets of metformin is liver. Therefore, if the hepatic expression of OCT1 and the distribution of metformin are influenced by obesity, the dosing regimen of metformin should be altered in obese patients. Here, we evaluate whether obesity modulates the expression of hepatic OCT1 and hepatic distribution of metformin in high-fat (HF) diet-induced obese (DIO) mice. We observed that various genes related with pharmacokinetics were changed by HF-DIO. More importantly, the hepatic OCT-1 expression was higher in HF DIO mice compared with lean control. Using the OCT-1 substrate, metformin, we observed that the hepatic distribution of metformin was significantly higher in mice fed a HF diet. In cellular experiment, the increased expression of OCT1 may be resulted from insulin and leptin which increase in obese condition. CONCLUSION – Our results suggest, at least in part, that obesity might have an effect on the pharmacokinetics of various drugs. In addition, absorption and distribution of substrate drugs for OCT-1 through an increase in hepatic expression of the protein. Further studies on the regulation of hepatic expression of these proteins in humans with morbid obesity and its clinical implications are warranted.