Effects of indomethacin and sulindac on hydrochlorothiazide kinetics

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Abstract
The influence of 2 nonsteroidal anti-inflammatory drugs, indomethacin and sulindac, on the diuretic effect and kinetics of hydrochlorothiazide was investigated in healthy subjects. In an open, randomized, crossover study, 8 healthy subjects were treated with hydrochlorothiazide, 50 mg a day, for 4 wk. In the 2nd and 4th wk, indomethacin, 25 mg 3 times a day, or sulindac, 200 mg twice a day, were added. Blood pressure, body weight, plasma levels of K, creatinine and albumin the hematocrit, plasma renin activity (PRA), and the 24-h urinary excretion of Na and K 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 h after HCTZ dosing. When indomethacin was added to hydrochlorothiazide, body weight and plasma K 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 2 subjects who had somewhat lower endogenous creatinine clearance values than the other subjects. Except for a decrease in PRA, there were no dynamic interactions. An interaction between indomethacin and hydrochlorothiazide apparently is caused by dynamic mechanisms such as inhibition of renal prostaglandin synthesis, whereas sulindac may alter the renal clearance of hydrochlorothiazide.