Effects of the EGFR Inhibitor Erlotinib on Magnesium Handling

Abstract

A mutation in pro-EGF causes isolated hypomagnesemia, and monoclonal antibodies targeting the extracellular domain of the EGF receptor (EGFR) affect epithelial Mg 2ϩ transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg 2ϩ homeostasis, however, remains unknown. Here, we injected C57BL/6 mice with erlotinib for 23 days and observed a small but significant decrease in serum Mg handling but its effect on the systemic Mg 2ϩ concentration seems less potent than that observed with antibody-based EGFR inhibitors. These data suggest that typical human dosages of erlotinib are unlikely to severely affect serum Mg 2ϩ concentrations.

Renal Control of Calcium, Phosphate, and Magnesium Homeostasis

“…Although proton pump inhibitors most likely cause impaired intestinal magnesium absorption, most of the other drugs associated with hypomagnesemia impair renal tubular magnesium reabsorption by direct or indirect inhibition of magnesium reabsorption in the thick ascending limb or the distal convoluted tubule (102,110,111).…”

Hypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents

“…Although these drugs may induce hypomagnesaemia, the lack of severity effect on serum Mg 2+ concentration seems to be related to the typical human doses of these small molecules, as it was shown by Dinke et al in an experimental data [28]. Using a C57BL/6 mice and HEK293 cells expressing TRPM6 treated with different concentrations of erlotinib, they established that erlotinib is able to influence Mg 2+ handling but its effect on the serum Mg 2+ concentration seems less potent than that observed with anti-EGFR antibodies [28]. Although EGFR tyrosine kinase inhibitors have also the potential to induce hypomagnesaemia, the usual human doses seem to be insufficient to induce this side effect.…”

Regulation of Mg2+ Reabsorption and Transient Receptor Potential Melastatin Type 6 Activity by cAMP Signaling

“…4,6,16,17,19,24 TRPM6 undergoes autophosphorylation, 24,25 which leads to a shift in the inhibition by intracellular Mg 2+ /Mg 2+ nucleotides to higher concentrations. 17 In the kidneys, TRPM6 is regulated by the EGF, [26][27][28] insulin, 29 estrogens, 30,31 purinergic signaling, 32 dietary Mg 2+ intake, 30 and acid-base status. 33 Previous studies have suggested increased DCT Mg 2+ reabsorption in response to hormones such as parathyroid hormone (PTH), glucagon, calcitonin, and arginine vasopressin.…”