Effect of prolonged omeprazole administration on segmental intestinal Mg²⁺ absorption in male Sprague-Dawley rats

The exact mechanism of proton pump inhibitors (PPIs)-induced hypomagnesemia (PPIH) is largely unknown. Previous studies proposed that PPIH is a consequence of intestinal Mg²⁺ malabsorption. However, the mechanism of PPIs-suppressed intestinal Mg²⁺ absorption is under debate.

To investigate the effect of 12-wk and 24-wk omeprazole injection on the total, transcellular, and paracellular Mg²⁺ absorption in the duodenum, jejunum, ileum, and colon of male Sprague-Dawley rats.

The rats received 20 mg/kg∙d subcutaneous omeprazole injection for 12 or 24 wk. Plasma and urinary Mg²⁺, Ca²⁺, and PO₄ ^3- levels were measured. The plasma concentrations of 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), epidermal growth factor (EGF), and insulin were also observed. The duodenum, jejunum, ileum, and colon of each rat were mounted onto individual modified Using chamber setups to study the rates of total, transcellular, and paracellular Mg²⁺ absorption simultaneously. The expression of transient receptor potential melastatin 6 (TRPM6) and cyclin M4 (CNNM4) in the entire intestinal tract was also measured.

Single-dose omeprazole injection significantly increased the intraluminal pH of the stomach, duodenum, and jejunum. Omeprazole injection for 12 and 24 wk induced hypomagnesemia with reduced urinary Mg²⁺ excretion. The plasma Ca²⁺ was normal but the urinary Ca²⁺ excretion was reduced in rats with PPIH. The plasma and urinary PO₄ ^3- levels increased in PPIH rats. The levels of 1α,25(OH)₂D₃ and FGF-23 increased, whereas that of plasma EGF decreased in the omeprazole-treated rats. The rates of the total, transcellular, and paracellular Mg²⁺ absorption was significantly lower in the duodenum, jejunum, ileum, and colon of the rats with PPIH than in those of the control rats. The percent suppression of Mg²⁺ absorption in the duodenum, jejunum, ileum, and colon of the rats with PPIH compared with the control rats was 81.86%, 70.59%, 69.45%, and 39.25%, respectively. Compared with the control rats, the rats with PPIH had significantly higher TRPM6 and CNNM4 expression levels throughout the intestinal tract.

Intestinal Mg²⁺ malabsorption was observed throughout the intestinal tract of rats with PPIH. PPIs mainly suppressed small intestinal Mg²⁺ absorption. Omeprazole exerted no effect on the intraluminal acidic pH in the colon. Thus, the lowest percent suppression of total Mg²⁺ absorption was found in the colon. The expression levels of TRPM6 and CNNM4 increased, indicating the presence of a compensatory response to Mg²⁺ malabsorption in rats with PPIH. Therefore, the small intestine is an appropriate segment that should be modulated to counteract PPIH.