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

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 (EC50 0.69 ± 0.27 µM) compared with naproxen (EC50 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.

Preliminary Investigation of Side Effects of Polymyxin B Administration in Hospitalized Horses

“…The use of omeprazole prevented polymyxin E-induced nephrotoxicity in a rat model and was used in some horses concurrently to PolyB [32]. Metamizol on the other hand is reported to cause acute kidney injury in a low number of human patients and might have also influenced renal function in horses concurrently treated with this antipyretic drug in the present study [33]. No data exist on the influence of other concurrently used drugs such as anti-inflammatory, anticoagulant, and gastroprotective substances on the pharmacokinetics, therapeutic and side effects of PolyB.…”

Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database

“…Although one study reported that short-term use of metamizole did not affect renal function in healthy adults [56], little is known about the nephrotoxic potential of metamizole. In view of its growing popularity, it is important to further investigate the safety profile of metamizole in future studies, especially in older adults with comorbidities and comedications.…”

One hundred years of dipyrone (metamizole): the recent evidence on its safety

“…Other possible mechanisms that try to explain the metamizole effects involves the stimulation of cannabinoid receptors, action on the serotonergic and noradrenergic systems of descending pathways, or, even, action on the protein kinase c-dependent pathway [11].…”