Houttuynia cordata extract increased systemic exposure and liver concentrations of metformin through OCTs and MATEs in rats

The synergistic activity of Houttuynia cordata ethanol extract (HCT) and metformin combination in diabetic rats has been previously reported, but the fundamental causes remain unsolved. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) transport metformin to the liver and kidneys. Therefore, pharmacological activity and systemic exposure of metformin in HCT–metformin combination were determined from pharmacokinetic change and glucose‐lowering activity using in vitro HEK‐293 cells expressing human OCTs or human MATEs and in vivo rats. HCT inhibited human OCT2 and human MATE1‐mediated metformin transports in vitro. In in vivo rats, treatment with HCT and metformin for 28 days in rats (28MH rats) reduced the rat Oct2‐mediated renal excretion of metformin and thereby the increased systemic exposure of metformin compared with only metformin‐treated rats for 28 days (28M rats). In 28MH rats, rat Oct1‐mediated metformin uptake into the liver was enhanced, leading to an improved glucose‐lowering effect without hypoglycaemia compared with 28M rats. There was no impairment of renal function in HCT and metformin treatments. These results suggest that HCT–metformin combination therapy is applicable in terms of efficacy and safety.