The Pharmacologic and Biologic Roles of Transporters for Metformin
Abstract
Membrane transporters are widely expressed throughout the body, transporting nutrients, metabolites, toxins, and drugs across cellular membranes. In drug development, transporters are clinically important for drug absorption and disposition, and play significant roles in pharmacokinetics and treatment response. In addition, there is a growing interest in physiologic roles of transporters as polymorphisms in many drug transporters have been significantly associated with human diseases. Metformin is widely used as first-line treatment of type 2 diabetes. It exists primarily as a hydrophilic cation at physiological pHs, and therefore, membrane transporters are involved in its intestinal absorption, tissues distribution, and renal elimination. Multiple organic cation transporters play roles in the pharmacokinetics of metformin, and many of them play important roles in its pharmacological response, as mediators of metformin entry into target tissues. Here, we investigated transporters of metformin, with an emphasis on the pharmacological and biological roles of transporters in the intestine and liver. We characterized the human thiamine transporter (THTR-2; SLC19A3), which plays a major role in the intestinal absorption of thiamine (Vitamin B1). We found that human THTR-2 is capable of transporting other compounds including the drugs metformin and famotidine, and the neurotoxin MPP+. Other chemical agents including phenformin, chloroquine, verapamil, famotidine, amprolium, and…
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