PHARMACOKINETIC-DYNAMIC ANALYSIS OF THE INDOMETHACIN-FUROSEMIDE INTERACTION IN MAN

Abstract

Indomethacin decreased the natiuretic 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. Furosemide (40 and 20 mg) was administered to 8 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 per min (P < 0.02) and renal clearance of furosemide from 1.05 .+-. 0.23 to 0.60 .+-. 0.06 ml/kg per 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 per min. The total amount of furosemide delivered into the urine, or the time course of furosemide delivery after the 40 or 20 mg doses did not change with indomethacin pretreatment. Indomethacin significantly altered dose-response curves of furosemide. While the serum concentration-response curve of furosemide significantly shifted to the right, the urinary furosemide-response curve did not shift after indomethacin pretreatment. With both analyses, maximal response decreased. Indomethacin altered furosemide disposition and delivery into the urine. The pharmacokinetic drug interaction did not account for the inhibitory effect of indomethacin on the response to furosemide.