title: 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(2+) transport. The effect of the EGFR tyrosine kinase inhibitor erlotinib on Mg(2+) 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(2+) concentrations at days 16 and 23, but the fractional excretion of Mg(2+) remained unchanged after 23 days. Semiquantitative immunohistochemical evaluation did not reveal detectable changes in renal expression of transient receptor potential melastatin 6 (TRPM6) protein, the channel that mediates Mg(2+) reabsorption. Patch clamp analysis in TRPM6-expressing cells demonstrated that 30 muM erlotinib inhibited EGF-induced changes in TRPM6 current density and tyrosine phosphorylation of EGFR; 0.3 muM erlotinib did not have these effects. Furthermore, 30 muM erlotinib inhibited EGF-stimulated increases in the mobile fraction of endomembrane TRPM6 channels. In summary, erlotinib can influence Mg(2+) handling but its effect on the systemic Mg(2+) 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(2+) concentrations.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Henrik
authors.initials: H
authors.lastname: Dimke
authors.forename: Jenny
authors.initials: J
authors.lastname: van der Wijst
authors.forename: Todd R
authors.initials: TR
authors.lastname: Alexander
authors.forename: Inez M J
authors.initials: IM
authors.lastname: Meijer
authors.forename: Gemma M
authors.initials: GM
authors.lastname: Mulder
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Joost G
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: René J
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000818:Animals; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000069347:Erlotinib Hydrochloride; D008274:Magnesium / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011799:Quinazolines / Q000494:pharmacology*; D050053:TRPM Cation Channels / Q000187:drug effects / Q000502:physiology
chemical_list: D011799:Quinazolines; D050053:TRPM Cation Channels; C530168:Trpm6 protein, mouse; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D008274:Magnesium