Pharmacokinetic and pharmacodynamic interaction between furosemide and the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) may blunt anti-hypertensive effects and alter renal-function of loop-diuretics.1,2 An open-label study in healthy volunteers (N=40) compared the pharmacokinetic/pharmacodynamic (PK/PD) profiles of furosemide administered intravenously (IV) alone (20mg/2min) vs after oral ibuprofen (800mg TID), oral diclofenac sodium (75mg BID), or topical diclofenac epolamine topical patch 1.3% (DETP) BID.3 Dextrose (5% in water) administered IV at 2mL/2min served as negative control. NSAIDs were administered for 3 days followed by 20mg furosemide IV on day-4. Plasma furosemide and NSAID, and urine furosemide, sodium, potassium, and prostaglandin E2 (PGE2) concentrations were measured at multiple intervals through 24h after furosemide-dose. Interactions between NSAIDs and furosemide vs furosemide alone were concluded if 90% confidence intervals (CIs) for ratios of PK/PD measures fell outside 80%-125%. Ibuprofen yielded greater furosemide systemic-exposure (AUC0-t, % mean ratio 137.2 [CIs 131.7-143.0]; AUCinf, 136.1 [131.2-141.1]), and decreased total body-clearance (CL 73.5 [70.9-76.2]), renal-clearance (CLR 76.6 [72.4-81.1]), and maximum excretion-rate (Rmax 81.3 [76.7-86.1]). Ibuprofen increased urine sodium-excretion (Ae0-24) and decreased Rmax (p<0.01); mean ratios and 90% CI ranges supported an interactive effect with furosemide. Oral diclofenac sodium and DETP had no clinically significant effect on furosemide PK. Oral diclofenac sodium decreased urine-output (14%, p=0.005; Vu0-24 84.7 [76.9-93.2]). DETP did not affect furosemide PD in any clinically significant manner. Urine PGE2 concentrations fell below the level of quantification (30pg/mL) following furosemide-administration. At steady-state, systemic-exposure to diclofenac after DETP was <1% vs oral diclofenac sodium (16.0 vs 2164 ng•h/mL). Overall, oral ibuprofen affected furosemide PK and PD; oral diclofenac sodium affected PD; and DETP did not affect PK or PD in healthy subjects. Additional drug-interaction studies between NSAIDs and loop-diuretics are needed to identify interactions and determine clinical significance. Research supported by King Pharmaceuticals®, Inc. (1. Brater, Am J Medicine, 1986; 2. Müller, Eur J Clin Pharmacol, 1995; 3. Flector Patch PI, 2009). Nonsteroidal anti-inflammatory drugs (NSAIDs) may blunt anti-hypertensive effects and alter renal-function of loop-diuretics.1,2 An open-label study in healthy volunteers (N=40) compared the pharmacokinetic/pharmacodynamic (PK/PD) profiles of furosemide administered intravenously (IV) alone (20mg/2min) vs after oral ibuprofen (800mg TID), oral diclofenac sodium (75mg BID), or topical diclofenac epolamine topical patch 1.3% (DETP) BID.3 Dextrose (5% in water) administered IV at 2mL/2min served as negative control. NSAIDs were administered for 3 days followed by 20mg furosemide IV on day-4. Plasma furosemide and NSAID, and urine furosemide, sodium, potassium, and prostaglandin E2 (PGE2) concentrations were measured at multiple intervals through 24h after furosemide-dose. Interactions between NSAIDs and furosemide vs furosemide alone were concluded if 90% confidence intervals (CIs) for ratios of PK/PD measures fell outside 80%-125%. Ibuprofen yielded greater furosemide systemic-exposure (AUC0-t, % mean ratio 137.2 [CIs 131.7-143.0]; AUCinf, 136.1 [131.2-141.1]), and decreased total body-clearance (CL 73.5 [70.9-76.2]), renal-clearance (CLR 76.6 [72.4-81.1]), and maximum excretion-rate (Rmax 81.3 [76.7-86.1]). Ibuprofen increased urine sodium-excretion (Ae0-24) and decreased Rmax (p<0.01); mean ratios and 90% CI ranges supported an interactive effect with furosemide. Oral diclofenac sodium and DETP had no clinically significant effect on furosemide PK. Oral diclofenac sodium decreased urine-output (14%, p=0.005; Vu0-24 84.7 [76.9-93.2]). DETP did not affect furosemide PD in any clinically significant manner. Urine PGE2 concentrations fell below the level of quantification (30pg/mL) following furosemide-administration. At steady-state, systemic-exposure to diclofenac after DETP was <1% vs oral diclofenac sodium (16.0 vs 2164 ng•h/mL). Overall, oral ibuprofen affected furosemide PK and PD; oral diclofenac sodium affected PD; and DETP did not affect PK or PD in healthy subjects. Additional drug-interaction studies between NSAIDs and loop-diuretics are needed to identify interactions and determine clinical significance. Research supported by King Pharmaceuticals®, Inc. (1. Brater, Am J Medicine, 1986; 2. Müller, Eur J Clin Pharmacol, 1995; 3. Flector Patch PI, 2009).