J. Oh,1 S. Yi,1 A. Kim,1 S. Lee,1 J. Cho,1 S. Yoon,1 I. Jang,1 J. Chung2; 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, Republic of, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea, Republic of

BACKGROUND: Renal tubular secretion of metformin is mediated mainly via Multidrug And Toxin Extrusion (MATE) transporters at the apical membrane. We investigated the effect of MATE inhibition on the pharmacokinetics (PK) and pharmacodynamics (PD) of metformin.
METHODS: Twenty healthy male subjects received metformin 500 mg twice a day in each period; in the first period, metformin alone, in the second period, metformin with pyrimethamine 50 mg, a potent MATE inhibitor. Metformin concentrations in plasma and urine were determined using LC-MS/MS and PK parameters were calculated by non-compartmental method. PD of metformin was assessed in each period by oral glucose tolerance test (OGTT) before and after the metformin dose; the differences in area under the glucose concentration-time curve (ΔAUG0-3h), and the differences in maximum and 2 hour post OGTT glucose level (ΔGmax and ΔPP2) were calculated. General linear mixed effects model was used to compare metformin’s PK and PD parameters between treatment periods.
RESULTS: The metformin’s Cmax and AUC0-12h was increased and its renal clearance was lowered after pyrimethamine co-administrations; the geometric mean ratios (90% CI) of corresponding PK parameters were 2.58 (2.30, 2.89), 2.02 (1.79, 2.29) and 0.28 (0.25, 0.31), respectively. However, the PD parameters of metformin decreased after pyrimethamine co-administrations; the mean differences (90% CI) of ΔAUG0-3h, ΔGmax and ΔPP2 were -30.66 (-52.69, -8.62) mg*h/dL, -17.05 (-28.99, -5.11) mg/dL and -8.4 (-19.48, 2.68) mg/dL, respectively.
CONCLUSION: These findings indicate that pyrimethamine, a MATE transporter inhibitor, increases systemic exposure of metformin through decreasing its renal clearance, but it does not increase metformin’s blood glucose lowering action.