The Effect of Novel Promoter Variants in MATE1 and MATE2 on the Pharmacokinetics and Pharmacodynamics of Metformin

Abstract

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.−66T→C, rs2252281) and MATE2 (g.−130G→A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

Metformin Sinusoidal Efflux from the Liver Is Consistent with Negligible Biliary Excretion and Absence of Enterohepatic Cycling

“…Liver distribution was reduced up to 30-fold in mice lacking hepatic Oct1 (Wang et al, 2002). Clinically, OCT1 and MATE1 genetic polymorphisms resulted in altered metformin pharmacodynamics, consistent with the expected changes in hepatic drug exposure (Shu et al, 2007;Stocker et al, 2013). The active secretory component of metformin renal clearance, which accounts for approximately 80% of systemic clearance (glomerular filtration contributes approximately 20%), is mediated by OCT2 uptake into the renal proximal tubule followed by secretion into urine via MATE1 and MATE2-K (Gong et al, 2012).…”

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

“…In addition to drugdrug interaction studies, which have provided mechanistic information on the transporters involved in metformin renal elimination, human genetic studies have contributed immensely to our understanding of transporters involved in metformin renal elimination. In particular, in candidate gene studies in healthy volunteers, SLC22A2 and SLC47A1/SLC47A2 polymorphisms have been associated with changes in the pharmacokinetics and/or pharmacodynamics of metformin [54][55][56] .…”

“…In terms of metformin pharmacologic action, human genetic studies associating transporters and glycemic response have shown complex and somewhat contradictory results 41,54,[63][64][65] , which may due to differences in study design, sample size, and different end-point …”

Low Concentrations of Metformin Suppress Glucose Production in Hepatocytes through AMP-activated Protein Kinase (AMPK)*

“…After oral administration, the plasma concentration of metformin peaks within 1 h in humans and in animals (6 -8), achieving a plasma concentration of 10 -40 M in humans following a therapeutic dose (7,9). Because metformin is absorbed from the gastrointestinal tract and delivered directly to the liver through the portal vein, the plasma metformin concentration in the portal vein is somewhat higher (40 -80 M) (8).…”