Pharmacokinetic-dynamic analysis of the indomethacin-furosemide interaction in man

Indomethacin decreased the natriuretic response to furosemide. A possible mechanism of this effect of indomethacin, independent of prostaglandin synthetase inhibition, is a pharmacokinetic drug interaction in which indomethacin affects access of furosemide to its intratubular site of action. We administered 40 and 20 mg of furosemide to eight normal volunteers with and without pretreatment to eight normal volunteers with and without pretreatment with indomethacin. Furosemide concentration in serum and urine samples was measured by high performance liquid chromatography. Indomethacin significantly decreased plasma clearance of furosemide from 1.84 +/- 0.36 to 1.10 +/- 0.08 ml/kg/min (P < 0.2) and renal clearance of furosemide from 1.05 +/- 0.23 to 0.60 +/- 0.06 ml/kg/min (P < 0.05). The nonrenal clearance of furosemide decreased, but not significantly, from 0.80 +/- 0.17 to 0.50 +/- 0.10 ml/kg/min. Neither the total amount of furosemide delivered into the urine, nor the time course of furosemide delivery after the 40 or 20 mg doses changed with indomethacin pretreatment. Indomethacin significantly altered dose-response curves of furosemide. While the serum concentration-response curves of furosemide significantly shifted to the right, the urinary furosemide-response curve did not shift after indomethacin pretreatment. However, with both analyses, maximal response decreased. Indomethacin altered furosemide disposition and delivery into the urine. Nevertheless, this pharmacokinetic drug interaction did not account for the inhibitory effect of indomethacin on the response of furosemide.