A comparison of uptake of metformin and phenformin mediated by hOCT1 in human hepatocytes

Abstract

Metformin, a biguanide that has been used to treat type 2 diabetes mellitus, is reportedly transported into human hepatocytes by human organic cation transporter 1 (hOCT1). The objective of this study was to investigate differences in the hepatic uptake of metformin and phenformin, a biguanide derivative similar to metformin. Special focus was on the role of active transport into cells. Experiments were therefore performed using human cryopreserved hepatocytes and hOCT1 expressing oocytes. Both biguanides proved to be good substrates for hOCT1. However, phenformin exhibited a much higher affinity and transport activity, with a marked difference in uptake kinetics compared with metformin. Both biguanides were transported actively by hOCT1, with the active transport components much greater than passive transport components in both cases, suggesting that functional changes in hOCT1 might affect the transport of both compounds to the same degree. This study for the first time produced detailed comparative findings for uptake profiles of metformin and phenformin in human hepatocytes and hOCT1 expressing oocytes. It is considered that hOCT1 may not be the only key factor that determines the frequency of metformin and phenformin toxicity, considering the major contribution of this transporter to the total hepatic uptake and comparable width of their therapeutic concentrations.

Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta

“…Previously, phenformin has been used at a concentration of up to 10 mM to determine AMPK regulation in rat skeletal muscle [37]. In addition, phenformin has been shown to be rapidly transported in hepatocytes, compared with metformin [35]. In the present study ( Fig.…”

“…Importantly, Zhou et al have shown that in rat hepatocytes, metformin exhibits significant biological effects at 500 μM to 3 mM concentrations upon incubation for 1 to 3 hours [34]. This has been attributed to its slow membrane permeability / transport in hepatocytes [34, 35]. In the present study, we therefore incubated aortic rings with metformin at 10 μM to 3 mM concentrations for 30 min ( Fig.…”

Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions

“…Hepatic uptake by OCT1 and passive permeability in the liver were applied in the PerL model using estimates of intrinsic clearance and CL PD,liver , respectively, from experiments with cryopreserved human hepatocytes (Sogame et al, 2009). …”

Inhibition of Polo-like Kinase 1 (Plk1) Enhances the Antineoplastic Activity of Metformin in Prostate Cancer

“…More recently, another group reported that the inhibition of mTOR1 by metformin was due to the enhanced binding between PRAS40 and Raptor, both of which are components of mTORC1, thus independent of AMPK (20). The second concern is that intake of metformin into the cell requires the expression of OCT1 (organic cation transporter 1) (21,22), and the concentrations of metformin used in current in vitro or preclinical antiproliferative studies are much higher than the recommended therapeutic dose in humans (23). In other words, the positive results in animal studies cannot indicate success in clinical trials if we do not use a similar dose of metformin.…”