title: The effect of nonsteroidal agents (NSAIDs) on the pharmacokinetics and pharmacodynamics of metolazone.
abstract: NSAIDs attenuate the natriuretic response to loop diuretics. Their effect on the action of distal tubular diuretics is poorly explored. Accordingly, the pharmacokinetics and pharmacodynamics of metolazone [M], a distal tubular diuretic, with and without indomethacin [M+I] or sulindac [M+S] were examined in six healthy volunteers. Urine samples were obtained over 36 hours post-metolazone dosing for the determination of sodium, potassium and metolazone concentration. Though cumulative M excretion 750 +/- 247 [mucg/36 h] [M]; 749 +/- 239 [M+I]; 848 +/- 443 [M+S] was comparable between treatment groups, total sodium [Na+] excretion was significantly depressed in the presence of S or I, 685 +/- 114 [mEq/36 h] [M]; 454 +/- 90 [M+I] (p < or = 0.05); 553 +/- 123 [M+S] (p < or = 0.05). Peak Na+ excretion [muEq/min] was significantly decreased by I only and time to peak Na+ excretion did not differ amongst treatment groups. Total potassium [K+] excretion 160 +/- 39 [mEq/36 h] [M]; 111 +/- 53 [M+I] (p < or = 0.05); 135 +/- 31 [M+S] significantly decreased with I. This phenomenon was most evident between 12 and 36 hours. The administration of I or S with M significantly blunted sodium excretion on a purely pharmacodynamic basis while the decline in urinary potassium excretion upon addition of I to M related probably to an attenuation of braking phenomenon induced kaliuresis. These findings likely reflect NSAID-induced sodium reabsorption at loci prior to the site of action of metolazone.
authors.affiliation: Division of Nephrology, Virginia Commonwealth University, Medical College of Virginia, Richmond.
authors.forename: E B
authors.initials: EB
authors.lastname: Ripley
authors.forename: T W
authors.initials: TW
authors.lastname: Gehr
authors.forename: H
authors.initials: H
authors.lastname: Wallace
authors.forename: J
authors.initials: J
authors.lastname: Wade
authors.forename: C
authors.initials: C
authors.lastname: Kish
authors.forename: D A
authors.initials: DA
authors.lastname: Sica
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000450:Aldosterone / Q000097:blood; D004357:Drug Synergism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D007686:Kidney Tubules, Distal / Q000187:drug effects*; D008788:Metolazone / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000652:urine; D013467:Sulindac / Q000494:pharmacology*
chemical_list: D013467:Sulindac; D000450:Aldosterone; D012964:Sodium; D011188:Potassium; D008788:Metolazone; D007213:Indomethacin