Diabetes is a major health problem worldwide, and metformin, a traditional oral anti-hyperglycemic drug, is now believed to
be the most widely prescribed antidiabetic drug. Metformin acts primarily by inhibiting hepatic glucose production and improving insulin
sensitivity. Metformin is absorbed predominately by the small intestine and excreted in an unaltered form in the urine. The pharmacokinetics
of metformin is primarily determined by membrane transporters, including the plasma membrane monoamine transporter (PMAT),
the organic cation transporters (OCTs), the multidrug and toxin extrusion (MATE) transporters, and the critical protein kinase AMPactivated
protein kinase (AMPK). PMAT may play a role in the uptake of metformin from the gastrointestinal tract, while OCTs mediate
the intestinal absorption, hepatic uptake, and renal excretion of metformin. MATEs are believed to contribute to the hepatic and renal excretion
of the drug. The pharmacologic effects of metformin are primarily exerted in the liver, at least partly via the activation of AMPK
and the subsequent inhibition of gluconeogenesis. A considerable amount of pharmacogenetic research has demonstrated that genetic
variation is one of the major factors affecting metformin response. Moreover, it has become increasingly clear that membrane transporters
are important determinants of the pharmacokinetics of metformin. In this review, we will discuss the genetic variants of major transporters
that purportedly determine the pharmacokinetics of metformin in terms of drug bioavailability, distribution, and excretion, such as
PMAT, OCTs, and MATEs. Understanding how genetic variation affects metformin response will help promote more effective use of the
drug for the treatment of type 2 diabetes (T2D).
AMPK, MATE, metformin, OCT, pharmacogenetic, SNP, T2D.
Department of Pharmacy, Xijing Hospital, and The State Key Laboratory of Cancer Biology and The Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an, Shaanxi Province, 710032, People’s Republic of China.