Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects
Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects
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DOI：
10.1038/clpt.2011.36
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发表时间：
2011-06-01
影响因子：
6.7
通讯作者：
Sugiyama, Y.
中科院分区：
文献类型：
--
作者：
Kusuhara, H.;Ito, S.;Sugiyama, Y.
进行了二甲双胍微剂量研究，以研究治疗剂量（ThD）下药物-药物相互作用的可预测性。健康受试者以交叉方式口服二甲双胍微剂量（100 μ g）或ThD (250 mg)，加或不加强效竞争性多药和毒素挤出（MATE）抑制剂乙胺嘧啶（50 mg, p.o.）。乙胺嘧啶显著降低二甲双胍的肾清除率，微剂量组和四氢呋喃组分别降低23%和35%。在ThD，但在微剂量下，它引起二甲双胍的最大浓度（C(max)）和血浆浓度-时间曲线下面积（AUC）显著增加（分别为对照值的142和139%）。人小管膜囊显示乙胺抑制二甲双胍摄取。乙胺嘧啶不影响二甲双胍ThD后血浆乳酸/丙酮酸，但显著降低肾肌酐清除率，从而引起血浆肌酐水平升高。这项微剂量研究定量预测了一种药物-药物相互作用，涉及乙胺嘧啶对ThD时二甲双胍的肾脏清除。乙胺嘧啶是一种有效的体内MATE蛋白抑制剂。
A microdose study of metformin was conducted to investigate the predictability of drug-drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 mu g) or ThD (250 mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance of metformin by 23 and 35% at the microdose and ThD, respectively. At ThD, but not at microdose, it caused significant increases in the maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) of metformin (142 and 139% of control values, respectively). Human canalicular membrane vesicles showed pyrimethamine-inhibitable metformin uptake. Pyrimethamine did not affect plasma lactate/pyruvate after ThD of metformin but significantly reduced the renal clearance of creatinine, thereby causing elevation of plasma creatinine level. This microdose study quantitatively predicted a drug-drug interaction involving the renal clearance of metformin at ThD by pyrimethamine. Pyrimethamine is a useful in vivo inhibitor of MATE proteins.