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.
Highlights
Metamizole is an effective non-opioid analgesic and antipyretic drug. It has a favorable gastrointestinal safety profile, but there is a lack of data on its renal tolerability compared with classic nonsteroidal anti-inflammatory drugs (NSAIDs) (Farker et al, 1995; Zapater et al, 2015)
The reported half maximal inhibitory concentration (IC50) values for COXinhibition show high variability, ranging from 2.6 μmol/L to >400 μmol/L and mostly appear to be higher compared to corresponding IC50 values of non-selective NSAIDs such as ibuprofen (12–42 μmol/L) or naproxen (0.3–24 μmol/L) (Campos et al, 1999; Gierse et al, 1999; Hinz et al, 2007; Pierre et al, 2007; Rogosch et al, 2012)
Considering the increasing use of metamizole in many countries (Stammschulte et al, 2015) and the lack of study data on its effect on renal function, the primary aim of this study was to examine the effect of metamizole compared with the non-specific COX-inhibitor naproxen on renal function in healthy, salt-depleted, male volunteers
Summary
Metamizole (dipyrone) is an effective non-opioid analgesic and antipyretic drug. It has a favorable gastrointestinal safety profile, but there is a lack of data on its renal tolerability compared with classic nonsteroidal anti-inflammatory drugs (NSAIDs) (Farker et al, 1995; Zapater et al, 2015). Other proposed mechanisms of action are stimulation of endogenous cannabinoid receptors (Rogosch et al, 2012; Crunfli et al, 2015), involvement of glutamatergic mechanisms, inhibition of neurokinin-1 receptor or transient receptor potential ankyrin 1(TRPA1) channel mediated responses (Nassini et al, 2015), inhibition of the protein kinase C-dependent pathway (Siebel et al, 2004), and involvement of the descending serotonergic and noradrenergic systems (Gencer et al, 2015)
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