The role of organic cation transporters in the pharmacokinetics and pharmacodynamics of metformin
Abstract
Metformin, the most widely prescribed anti-diabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney and peripheral tissues. Although membrane transporters responsible for the liver and kidney uptake of metformin have been identified, the mechanism in which metformin enters peripheral tissues is not completely understood. Organic cation transporter 3 (OCT3, SLC22A3) transports metformin in vitro and is expressed ubiquitously. The goals of this research are to determine the role of OCT3 in metformin disposition and response, identify OCT3 inhibitors that could potentially result in clinical drug-drug interactions when co-administered with metformin, and develop a method to predict competitive and non-competitive inhibitors of transporters. \tIn this dissertation, we showed that ablation of Oct3 in mice results in dramatic changes in the pharmacokinetics of metformin. In particular, the apparent volume of distribution, clearance and bioavailability of metformin were decreased in Oct3 knockout mice. We also showed that Oct3 knockout mice had reduced response to metformin. Notably, the effect of metformin on glucose tolerance is reduced in mice lacking Oct3, and that a likely explanation for this is reduced metformin accumulation in peripheral sites such as adipose tissue. Analysis of data from healthy volunteers receiving metformin revealed that a reduced function OCT3 genetic variant associated with attenuated response…
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