Should Pharmacokinetic Safety Challenges Prevent Metformin Use in Patients With Cancer?
Abstract
In her recent letter to the editor, Dr Alice C. Ceacareanu cited the underutilization of metformin in insulin-resistant patients diagnosed with cancer and pointed to the potential survival benefit they may receive. One reason metformin may be underutilized is safety concerns related to chemotherapy regimens impairing renal function or drug–drug interactions reducing metformin’s clearance (CL) and leading to toxicity, the primary concern being fatal lactic acidosis resulting from high metformin concentrations. The physiochemical properties of metformin, low number of hydrogen bond acceptors, low molecular weight, low polar surface area, and a low partition coefficient make it a molecule that prefers aqueous environments and undergoes almost no passive diffusion across membranes. Additionally, metformin is cationic at physiologic pH and a substrate for cation transporters (CTs). Despite thorough CT expression in enterocytes, metformin’s absorption from the gut is almost entirely passive via the paracellular route. This is only possible because of the highly perfused thin epithelium of the gut’s vasculature. However, the consequence of this is highly variable bioavailability (F, mean 1⁄4 50%-60%, range 1⁄4 20%75%). Nonetheless, F’s variability has not been reported to cause clinically significant events. Once reaching the blood stream a substantial amount of metformin selectively accumulates in erythrocytes and wellperfused tissues that express CTs, including the liver, kidney,…
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