Effects of indomethacin and sulindac on hydrochlorothiazide kinetics

We investigated the influence of two nonsteroidal anti-inflammatory drugs, indomethacin and sulindac, on the diuretic effect and kinetics of hydrochlorothiazide in healthy subjects. In an open, randomized, crossover study, eight healthy subjects were treated with hydrochlorothiazide, 50 mg a day, for 4 weeks. In the second and fourth weeks, indomethacin, 25 mg three times a day, or sulindac, 200 mg twice a day, were added. Blood pressure, body weight, plasma levels of potassium, creatinine, and albumin, the hematocrit, plasma renin activity (PRA), and the 24-hour urinary excretion of sodium and potassium were measured at the end of each week. Plasma concentrations of hydrochlorothiazide and its urinary excretion were also determined 0.5, 1, 2, 3, 4, 8, 10, and 24 hours after HCTZ dosing. When indomethacin was added to hydrochlorothiazide, body weight and plasma potassium levels increased and PRA decreased. Hydrochlorothiazide kinetics were not influenced. In contrast, sulindac decreased the renal clearance of hydrochlorothiazide and increased hydrochlorothiazide plasma levels in two subjects who had somewhat lower endogenous creatinine clearance values than the other subjects. Except for a decrease in PRA, there were no dynamic interactions. Our results suggest that an interaction between indomethacin and hydrochlorothiazide is caused by dynamic mechanisms such as inhibition of renal prostaglandin synthesis, whereas sulindac may alter the renal clearance of hydrochlorothiazide.