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Comparative Effects of Metamizole (Dipyrone) and Naproxen on Renal Function and Prostacyclin Synthesis in Salt-Depleted Healthy Subjects - A Randomized Controlled Parallel Group Study.

Authors :
Blaser LS
Duthaler U
Bouitbir J
Leuppi-Taegtmeyer AB
Liakoni E
Dolf R
Mayr M
Drewe J
Krähenbühl S
Haschke M
Source :
Frontiers in pharmacology [Front Pharmacol] 2021 Sep 07; Vol. 12, pp. 620635. Date of Electronic Publication: 2021 Sep 07 (Print Publication: 2021).
Publication Year :
2021

Abstract

Aim: The objective was to investigate the effect of metamizole on renal function in healthy, salt-depleted volunteers. In addition, the pharmacokinetics of the four major metamizole metabolites were assessed and correlated with the pharmacodynamic effect using urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1α. Methods: Fifteen healthy male volunteers were studied in an open-label randomized controlled parallel group study. Eight subjects received oral metamizole 1,000 mg three times daily and seven subjects naproxen 500 mg twice daily for 7 days. All subjects were on a low sodium diet (50 mmol sodium/day) starting 1 week prior to dosing until the end of the study. Glomerular filtration rate was measured using inulin clearance. Urinary excretion of sodium, potassium, creatinine, 6-keto-prostaglandin F1α, and pharmacokinetic parameters of naproxen and metamizole metabolites were assessed after the first and after repeated dosing. Results: In moderately sodium-depleted healthy subjects, single or multiple dose metamizole or naproxen did not significantly affect inulin and creatinine clearance or sodium excretion. Both drugs reduced renal 6-keto-prostaglandin F1α excretion after single and repeated dosing. The effect started 2 h after intake, persisted for the entire dosing period and correlated with the concentration-profile of naproxen and the active metamizole metabolite 4-methylaminoantipyrine (4-MAA). PKPD modelling indicated less potent COX-inhibition by 4-MAA (EC <subscript>50</subscript> 0.69 ± 0.27 µM) compared with naproxen (EC <subscript>50</subscript> 0.034 ± 0.033 µM). Conclusions: Short term treatment with metamizole or naproxen has no significant effect on renal function in moderately sodium depleted healthy subjects. At clinically relevant doses, 4-MAA and naproxen both inhibit COX-mediated renal prostacyclin synthesis.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2021 Blaser, Duthaler, Bouitbir, Leuppi-Taegtmeyer, Liakoni, Dolf, Mayr, Drewe, Krähenbühl and Haschke.)

Details

Language :
English
ISSN :
1663-9812
Volume :
12
Database :
MEDLINE
Journal :
Frontiers in pharmacology
Publication Type :
Academic Journal
Accession number :
34557087
Full Text :
https://doi.org/10.3389/fphar.2021.620635