Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors

Abstract

The tubular secretion of diuretics in the proximal tubule has been shown to be critical for the action of drugs. To elucidate the molecular mechanisms for the tubular excretion of diuretics, we have elucidated the interactions of human organic anion transporters (hOATs) with diuretics using cells stably express-ing hOATs. Diuretics tested were thiazides, including chlorothi-azide, cyclothiazide, hydrochlorothiazide, and trichlormethia-zide; loop diuretics, including bumetanide, ethacrynic acid, and furosemide; and carbonic anhydrase inhibitors, including acet-azolamide and methazolamide. These diuretics inhibited or-ganic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4 in a competitive manner. hOAT1 exhibited the highest affinity interactions for thiazides, whereas hOAT3 did those for loop diuretics. hOAT1, hOAT3, and hOAT4 but not hOAT2