Modeling and simulation of the effect of proton pump inhibitors on magnesium homeostasis. 1. Oral absorption of magnesium.
Prolonged use of proton pump inhibitors has reportedly caused rare clinically symptomatic hypomagnesemia. A review of the literature suggests PPI drugs may impair intestinal magnesium absorption. With the goal of preventing PPI-induced hypomagnesemia, an oral absorption-centric model was developed by referencing literature data. Our modeling with human data reveals that magnesium absorption is substantial in the distal intestine. We then perform simulations by referring to the reported reduction in mid to distal intestinal pH caused by one week of oral esomeprazole, and to reported reduction of the divalent cation-sensitive current when the carboxyl side chains of glutamic and aspartic residues in the binding channels of TRPM6/TRPM7 were neutralized. Our simulations reveal that short-term PPI therapy may cause a very small reduction (5%) in the serum magnesium level, which is qualitatively consistent with the reported 1% reduction in magnesium absorption following 1 week of omeprazole in humans. Simulations provide insight into the benefit of frequent but small dose of magnesium supplementation in maintaining the serum magnesium level when magnesium deficiency occurs.
Office of Generic Drugs, Office of Pharmaceutical Science, §Office of Pharmacovigilance and Epidemiology, Office of Surveillance and Epidemiology, and †Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation, Food and Drug Administration , Rockville, Maryland, United States.
Jane P F
JP
Bai
Ethan
E
Hausman
Robert
R
Lionberger
Xinyuan
X
Zhang
D000284:Administration, Oral; D003198:Computer Simulation; D006706:Homeostasis; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008274:Magnesium / Q000378:metabolism / Q000493:pharmacokinetics*; D008275:Magnesium Deficiency / Q000188:drug therapy* / Q000378:metabolism*; D008954:Models, Biological; D009853:Omeprazole / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D050053:TRPM Cation Channels / Q000378:metabolism; D014018:Tissue Distribution
D054328:Proton Pump Inhibitors; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D008274:Magnesium; D009853:Omeprazole