Dipyrone metabolite 4-MAA induces hypothermia and inhibits PGE2 -dependent and -independent fever while 4-AA only blocks PGE2 -dependent fever.

BACKGROUND AND PURPOSE: The antipyretic and hypothermic prodrug dipyrone prevents PGE2 -dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects. EXPERIMENTAL APPROACH: Male Wistar rats were treated i.p. with indomethacin (2 mg·kg(-1) ), dipyrone, 4-methylaminoantipyrine (4-MAA), 4-aminoantipyrine (4-AA) (60-360 mg·kg(-1) ), 4-formylaminoantipyrine, 4-acethylaminoantipyrine (120-360 mg·kg(-1) ) or vehicle 30 min before i.p. injection of LPS (50 µg·kg(-1) ), Tsv (150 µg·kg(-1) ) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE2 concentrations were determined in the CSF and hypothalamus by elisa. KEY RESULTS: In contrast to LPS, Tsv-induced fever was not followed by increased PGE2 in the CSF or hypothalamus. The antipyretic time-course of 4-MAA and 4-AA on LPS-induced fever overlapped with the period of the highest concentrations of 4-MAA and 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE2 increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia. CONCLUSIONS AND IMPLICATIONS: The presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE2 -independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone.

Simultaneous determination of dipyrone metabolites in rat hypothalamus, cerebrospinal fluid and plasma samples by LC-MS/MS.

BACKGROUND: After oral administration dipyrone is rapidly hydrolyzed to 4-methylaminoantipyrine, which is absorbed and further metabolized to 4-formylaminoantipyrine and to 4-aminoantipyrine, which is acetylated by a polymorphic N-acetyltransferase system to 4-acetylaminoantipyrine. To evaluate the presence of dipyrone metabolites in different rat matrices after intraperitoneal administration, an analytical method was developed and validated. METHODOLOGY: The four main dipyrone metabolites were extracted from plasma, cerebrospinal fluid and hypothalamus samples by LLE prior to LC-MS/MS. RESULTS: Standard calibration graphs for all metabolites were linear (r > 0.99). The intra- and inter-day precision and accuracy values were both inferior to 15%. CONCLUSION: This method is simple and specific for studying dipyrone metabolites after intraperitoneal administration.

Cerebrospinal fluid and plasma concentrations of dipyrone metabolites after a single oral dose of dipyrone.

OBJECTIVE: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically. METHODS: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly. RESULTS: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA. CONCLUSION: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.