Oral delivery of metformin: unravelling the role of intestinal transporters

Abstract

Oral metformin is the most prescribed therapy for type 2 diabetes mellitus, nevertheless, the bioavailability remains low and variable. The absorption of metformin from the GIT is incomplete. This review synthesises current evidence on the intestinal mechanisms governing metformin uptake, focusing on the roles of cation-selective solute carrier transporters and paracellular pathways. Metformin’s hydrophilicity, ionised state at physiological pH, and negligible passive permeability across GIT membranes necessitate the transporter-mediated entry. The regional expression and localisation of metformin-carrying transporters in native human intestine remains inconsistently reported. Increasing data support a substantial contribution of claudin-2-mediated tight-junction transport, while its input in total absorption is unclear. Genetic polymorphisms, drug interactions, and formulation factors further modulate exposure. The impact of co-administration with other agents, on metformin exposure is reviewed. Understanding permeation mechanisms is essential for optimising metformin bioavailability, and in search for approaches to increase its therapeutic performance.

Introduction

According to the World Health Organisation, globally 14.0% of adults aged 18 years and older are living with diabetes, of these more than 95.0% with Diabetes mellitus type 2 (DM2) [1]. Additionally, at least 64 million adults in Europe have diabetes, of these at least 90.0% are DM2 patients. It is estimated that 1 of 3 people are living with undiagnosed diabetes [1].

Metformin hydrochloride (metformin) is an antihyperglycemic agent which belongs to the medication class of biguanides and is the most used drug among DM2 patients. In some cases, metformin is also used in diabetes mellitus type 1 patients, as its’ effects include decreased hepatic gluconeogenesis, glucose absorption and triglyceride levels in the blood as well as increased insulin sensitivity [[2], [3], [4], [5]]. 83.6% of DM2 patients in the United Kingdom are prescribed metformin, while metformin is prescribed for 77.0% of DM2 patients in the United States [6,7]. For commercial use, metformin is only available in oral formulations; tablets, solution and powder for oral solution [8]. Metformin exhibits low and variable oral bioavailability, due to incomplete intestinal absorption. It is negligibly bound to plasma proteins and is distributed into various tissues. Metformin undergoes virtually no metabolism and is eliminated unchanged by the kidneys. The urinary and faecal elimination of metformin pollutes aqueous environments, causing adverse effects in fish and small aquatic organisms [9].

Metformin uptake is strongly influenced by the activity of transporters in the gastrointestinal tract (GIT), as well as paracellular intestinal uptake [10]. Membrane-bound transporters in the GIT modulate the permeation of various molecules, including, therapeutic drugs, from the intestinal lumen and may consequently contribute to their absorption into the systemic circulation. The main physiological functions of transporters are to transport nutrients from food or endogenous sources into the cells and the blood stream, and to provide protection from environmental toxins or substance build-up within the body by effluxing such substance back into the intestinal lumen. By determining which transporters are present in the GIT, studying which substrates they transport and subsequently the structures of those substrates, the transporters can be targeted when formulating drugs for oral administration – to optimise permeability, absorption, bioavailability and therapeutic efficacy [11].

The aim of this literature research is to identify, categorise and describe the transporters in the GIT which transport metformin into the blood and to identify inhibiting and propagating factors in order to build a theoretical basis for increased efficiency of metformin transport from the GIT to the blood stream. Improved metformin bioavailability is crucial to provide effective therapy, and minimize economic losses and environmental pollution, caused by incomplete intestinal absorption.

Continue reading here

Lilly Aurora Haydon, Andrejs Sitovs, Valentyn Mohylyuk, Oral delivery of metformin: unravelling the role of intestinal transporters, Journal of Drug Delivery Science and Technology, Volume 127, Part 1, 2027, 108856, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108856.

Read more interesting articles on Diabtes here:

• Development and Formulation of Anti-diabetic Capsules Containing Extract of E. denticulatum: Physicochemical Study, Encapsulation, and Release Kinetics
• Effect of engineered mesoporous silica particles with tailored pore size on glycaemic control in individuals with prediabetes or type 2 diabetes: a randomised, double-blind, placebo-controlled SHINE trial
• Protective effects of berberine-loaded chitosan/solid lipid nanoparticles in streptozotocin-induced gestational diabetes mellitus rats