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Randomized, open-label, 5-way crossover study to evaluate the pharmacokinetic/pharmacodynamic interaction between furosemide and the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen in healthy volunteers

C.A. Paterson, D. Jacobs, S. Rasmussen, S.P. Youngberg and N. McGuinness

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Volume 49 p. 477 - 484

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 8/2011 (477-490)

C.A. Paterson¹, D. Jacobs², S. Rasmussen³, S.P. Youngberg³ and N. McGuinness²

¹Pfizer, Inc., Cary, NC, ²Pfizer, Inc., Bridgewater, NJ, and ³Celerion, Inc., Lincoln, NE, USA
Objective: Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce renal complications in patients taking loop diuretics. This study investigated the pharmacokinetic/pharmacodynamic effects and safety profile of orally administered diclofenac sodium, ibuprofen and diclofenac epolamine topical patch (DETP) on furosemide in healthy adult subjects. Methods: This open-label, randomized, 5-way crossover study was conducted in 40 subjects (aged 19 – 45 y). Diclofenac (75 mg taken orally twice daily), DETP (1.3% applied topically twice daily), or ibuprofen (800 mg taken orally thrice daily) was administered for 3 consecutive days, followed by co-administration with furosemide (given intravenously as 20 mg/2 min). Plasma furosemide and NSAID concentrations, urine furosemide, sodium and potassium concentrations and urine output were determined throughout the 24 h period following furosemide administration. Results: Orally administered ibuprofen significantly increased furosemide AUC_0–t (37%) and AUC_0–inf (36%) and decreased total body CL (27%), R_max (19%) and CL_R (23%) geometric mean ratios compared with furosemide control. Oral and topical diclofenac had no pharmacokinetic effects on furosemide. Ibuprofen increased sodium excretion (Ae_0–24, 16%) and decreased sodium R_max (15%), and oral diclofenac decreased urine output (Vu_0–24, 15%). DETP had no effect on furosemide pharmacodynamics; total systemic exposure to diclofenac during DETP treatment was < 1% that of oral diclofenac. Treatments were generally safe, with 25 subjects reporting a total of 112 adverse events. Conclusions: Pharmacodynamic effects were seen with oral diclofenac (urine output) and ibuprofen (urine sodium excretion). Furosemide also affected plasma and urine pharmacokinetic profiles. Pharmacologic effects of DETP on furosemide were not observed under these conditions. Additional research is warranted to delineate the potential interactions of other NSAIDs with furosemide and other loop diuretics.Correspondence to:
Dr. D. Jacobs
Senior Director of Pfizer, Inc.
400 Crossing Boulevard
Bridgewater, NJ 08807, USA
Email: [email protected]

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