Effect of loperamide on Na+/D-glucose cotransporter activity in mouse small intestine

The mu-opioid agonist loperamide is an antidiarrhoeal drug which inhibits intestinal motility and secretion. Its anti-absorptive effects are less well investigated, but may be mediated through calmodulin. We have investigated further the effect of loperamide on the intestinal Na+-dependent D-glucose transporter (SGLT1). Brush-border membrane vesicles were prepared from mouse small intestine, and uptake of [3H]glucose was measured. Na+-dependent glucose uptake displayed the typical overshoot at 34 s; the peak value was 1.6 nmol mg(-1). The overshoot disappeared in the presence of phlorizin or when Na+ was replaced by K+. Extravesicular loperamide dose-dependently inhibited SGLT1 activity with an IC50 value of 450 micromol L(-1). Loperamide displayed a mixed inhibition type: the apparent Vmax decreased from 0.9 to 0.5 nmol mg(-1)/15 s, the apparent Km increased from 0.23 to 1.13 mmol L(-1) glucose. Na+ kinetics were more complex, but loperamide inhibited net glucose uptake by 90% at 100 mmol L(-1) Na+. Glucose uptake was unchanged by agents affecting calmodulin activity. Loperamide inhibited intestinal Na+, K+-ATPase activity, whilst sucrase activity was unaffected. SGLT1 activity was inhibited by loperamide, but this effect was not mediated through calmodulin. As this action is only evident at high concentrations of loperamide a nonspecific mechanism may be involved.