Physicochemical and pharmacokinetic properties of metformin hydrochloride

Metformin hydrochloride is a widely used biguanide derivative antidiabetic agent for the treatment type 2 diabetes mellitus. Metformin does not improve insulin secretion and produce normally hypoglycemia. Metformin decreases blood glucose levels by increasing skeletal muscle uptake of glucose, decreasing gluconeogenesis and absorption of glucose. Metformin has been found to be effective in the treatment of especially prostate, colon and breast cancer. Also, it is reported that metformin treatment decreases the risk of developing type 2 diabetes mellitus in women with polycystic ovarian syndrome. Metformin has a cationic charge at physiological pH and has very limited passive diffusion across cell membranes. According to Biopharmaceutics Classification System, metformin hydrochloride is a class 3 drug with high solubility and low permeability properties. Its absorption is slow and incomplete, and thus has low bioavailability (50-60%) following oral administration. Metformin is a substrate of organic cation transporters 1, 2 and 3 (OCT1-3) and its oral absorption, hepatic uptake and renal excretion occur mainly via these transporters. Membrane monoamine transporter (PMAT) expressed in human intestine may play a role in the intestinal absorption of metformin. Additionally, metformin is a good substrate for human multidrug and toxin extrusion 1 (MATE1) and MATE2-K. Metformin displays flip-flop kinetics (in human t1/2, po/t1/2, iv =4.1) after oral administration. Its binding to human plasma proteins is negligible after absorption. Metformin accumulates in the kidney, salivary glands and walls of the small intestine, and it has a large apparent volume of distribution. The average elimination half-life in plasma is about 6 hours. Metformin is not metabolized, and it is eliminated from the body by tubular secretion and excreted unchanged in the urine. Physicochemical, pharmacological, and pharmacokinetic properties of metformin will be reviewed this chapter.