Influences of drug transporters on Metformin's pharmacokinetics, pharmacodynamics and drug-drug interaction

Abstract

The biguanide derivative, metformin, is the first-line oral hypoglycemic drug for the treatment of type 2 diabetes. Its primary action is to lower hepatic glucose production by inhibiting gluconeogenesis. Generally, the change of drug transporter activity influences its drug exposure in systemic circulation by altering drug absorption and drug excretion especially in biliary and renal excretion. Meanwhile, drug transporting activity into action sites has been known to play important roles in drug actions. Metformin is a substrate of organic cation tranasporters (OCTs) and multidrug and toxin extrusion 1 (MATE1). OCT1 is a transporter located primarily in hepatocyte sinusoidal membranes, whereas OCT2 is localized mainly in the basolateral membrane of the kidney proximal tubule. MATE1 is an H+/organic cation antiporter on the apical membrane of kidney tubules and on bile canaliculi. Since OCT1 is located in the drug action site, metformin may play an important role in lowering glucose. OCT2 and MATE1 may affect metformin’s pharmacokinetics due to its location. There is controversy on pharmacogenetic difference of OCT2 (rs 316019) in metformin’s renal clearance and plasma concentration. Because of the location of MATE1, metformin may play a more important role than OCT2 does. I investigated the role of OCT2 and MATE1 on metformin’s pharmacokinetics and renal clearance through a genotype-enriched prospective clinical trial. OCT1 is related to the hepatic uptake of metformin and is associated with pharmacological action and adverse drug reaction. In this thesis, I investigated how OCT1 works with metformin to lower glucose effect by co-administering rifampin, an OCT1 inducer, and verapamil, and OCT1 inhibitor, with metformin. My thesis is composed of three parts. To assess the influences of polymorphisms MATE1 (rs 2252281) and OCT2 (rs 316019) on metformin’s pharmacokinetics and renal clearance, I conducted a genotype enriched-clinical trial in 48 subjects in Study I by balancing the MATE1 and OCT2 genotypes. In the latter two parts, I evaluated the influence of OCT1 on metformin’s glucose lowering effect in Study II and III. Study II assessed the change in metformin’s glucose lowering effect and metformin’s pharmacokinetics before and after rifampin, an OCT1 inducer, administration. Study III evaluated the change in metformin’s pharmacokinetics and metformin’s glucose lowering effect with and without verapamil administration. Metformin’s glucose effect was calculated by comparing the difference of oral glucose tolerance test (OGTT) before and after metformin administration. Three parameters were used to assess the metformin’s glucose lowering effect. Maximum glucose lowering effect (Gmax) was determined and area under the serum glucose concentration-time curve (ΔAUCgluc) was calculated using the trapezoidal rule. ΔAUCgluc60 was defined as area under the glucose curve from 0 to 60 minutes after glucose ingestion, during which serum glucose concentration increased. Metformin’s pharmacokinetic parameters were evaluated as Cmax, Tmax, AUCmet and t1/2 for plasma pharmacokinetic parameters and renal clearance (CLR) of metformin, Creatinine clearance (CLCr) and renal secretion of metformin (SrCLR) for urine pharmacokinetic parameters.In study I, plasma pharmacokinetic parameters (Cmax, Tmax, AUCmet and t1/2) are not significantly different by MATE1 and OCT2 genotypes. Renal clearance and net tubular secretion of metformin were significantly different by MATE1 genotype (CLR: 617±126 vs. 556±106 vs. 507±104 ml/min, P=0.031 and SrCLR: 517±121 vs. 456±107 vs. 399±107 ml/min, P=0.017). In study II, I found that rifampin increased Gmax by 41.9% (P=0.024) and ∆AUCgluc60 by 54.5% (P=0.020). Renal clearance of metformin was increased 16% by rifampin (P=0.008), and systemic exposure of metformin was slightly increased (13%, P=0.049), possibly due to increased absorption. Rifampin increased OCT1 mRNA levels 4.1-fold in peripheral blood cells (P=0.001). In study III, Verapamil treatment decreased mean Gmax by 62.5% (16 mg/dl vs. 6 mg/dl; P = 0.010). The glucose lowering effect of metformin was not observed after verapamil treatment in mean ΔAUCgluc60 levels (594±500 mg/dl•min vs. -6±556 mg/dl•min; P = 0.008) and mean ΔAUCgluc levels (509±1224 mg/dl•min vs. -702±1103 mg/dl•min; P = 0.015). Pharmacokinetic parameters, AUC, Cmax, CLR and SrCLR of metformin did not change when treated with verapamil.OCT1 plays a key role in metformin’s glucose-lowering effect. OCT1 based drug-drug interaction is important in the response of metformin presumably by affecting the effective concentration of metformin in the target organ. The important drug transporter on metformin’s renal clearance and secretion is not OCT2, but the MATE1 polymorphism (rs2252281).