Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics

Abstract

Metformin, a synthetic biguanide, is currently one of the most frequently recommended medications for type 2 diabetes treatment around the world. This review presents the latest discoveries in the pharmacokinetics of metformin, especially the role of transporters (e.g. Organic Cation Transporters OCTs, Multidrug and Toxin Extrusion transporters MATE) in oral absorption, distribution, elimination and biochemical effects of metformin in humans. We also review the associations between genetic variations of metformin transporters, their pharmacokinetics and drug efficacy or drug responses. In the second part of this paper, we highlight the current knowledge on novel metformin actions including favourable effects on lipid profile (e.g. decreasing plasma triglycerides (TG) and low density lipoprotein (LDL) cholesterol levels) and the cardiovascular system (e.g. decline in systolic and diastolic blood pressure, and vasoprotective effects). Furthermore, we provide an up-to-date overview of multidirectional activities of metformin, including the effects on coagulation and fibrinolysis, polycystic ovary syndrome, as well as the anti-ageing and antiinflammatory properties. Over the past two decades, metformin's antineoplastic properties have been drawing increasing attention of scientists; herein, we outline the state-of-the-art discoveries concerning metformin use in the field of oncology. Finally, we review the newly synthesized derivatives and pro-drugs of metformin and other biguanides.

Novel therapies for diabetes mellitus in pregnancy

“…Metformin is a biguanide that decreases hepatic glucose output, decreases intestinal glucose absorption, and increases peripheral glucose uptake in muscles and adipocyte cells 50. Metformin is a hydrophilic compound with low molecular weight and low binding capacity to plasma proteins, and trans-placental passage occurs in a dose dependent manner that is most likely carrier dependent 51.…”

Effect of exercise on key pharmacokinetic parameters related to metformin absorption in healthy humans: A pilot study

“…Its low lipophilicity does not favor absorption from the small intestine by rapid passive diffusion across cell membranes; consequently, its bioavailability is low, with a mean value of 55% . Therefore, researchers try to modify the formulation of metformin to enhance its bioavailability . The most common side effect of metformin is gastrointestinal distress.…”

“…6 Therefore, researchers try to modify the formulation of metformin to enhance its bioavailability. 8 The most common side effect of metformin is gastrointestinal distress. Hypoglycemia and lactic acidosis are rare, and the latter mainly occurs in patients with renal failure.…”

Pleiotropic Activity of Metformin and Its Sulfonamide Derivatives on Vascular and Platelet Haemostasis

“…The associations between T2DM and concomitantly occurring haemostasis disturbances, including thrombosis and the activation of blood coagulation are widely known [1]. Lipiński and Pretorius [2] divide the characteristic haemostatic abnormalities in T2DM into those occurring in stages of coagulation: thrombus formation, impaired fibrinolysis, endothelial dysfunction and platelet hyperreactivity.…”

“…For instance, it was reported that platelets in diabetes subjects are characterized by hyperreactivity, increased adhesiveness, exaggerated aggregation and changed metabolism [3]. T2DM patients can also present a pro-coagulation state following increased activity of coagulation factors such as fibrinogen, vWF, or factor FVII [1]. In T2DM patients, increased fibrin levels and thrombin generation have also been reported [3].…”