In various clinical situations a poor diuretic response to furosemide may be improved by the addition of metolazone. The mechanism of this additive effect is unclear. The purpose of the present investigation was to establish whether metolazone changes the pharmacokinetics of furosemide and by this mechanism enhances the diuretic effect. Eight volunteers were given an intravenous infusion of 4 mg h-1 of furosemide for 12 h. After 6 h 2.5 mg metolazone were administered orally. The addition of metolazone increased diuresis, urinary excretion of sodium and chloride (P less than 0.01), but decreased urinary excretion of calcium (P less than 0.01), while furosemide excretion remained unchanged. Total body clearance and renal clearance values of furosemide were similar before and after administration of metolazone. Our data confirm the additive diuretic effect of the combination treatment metolazone-furosemide and show for the first time a distinct hypocalciuric action of metolazone, similar to thiazides. Moreover metolazone does not affect the pharmacokinetics of furosemide.