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


METHODS
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.


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
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.
Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
David do C
Ddo C
Malvar
Fernando A
FA
Aguiar
Artur de L L
Ade L
Vaz
Débora C R
DC
Assis
Miriam C C
MC
de Melo
Valquíria A P
VA
Jabor
Evanguedes
E
Kalapothakis
Sérgio H
SH
Ferreira
Giuliano C
GC
Clososki
Glória E P
GE
de Souza
D000675:Ampyrone / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D058633:Antipyretics / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D015232:Dinoprostone / Q000134:cerebrospinal fluid / Q000378:metabolism*; D004177:Dipyrone / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics; D017208:Rats, Wistar; D012604:Scorpion Venoms
D058633:Antipyretics; D008070:Lipopolysaccharides; D011355:Prodrugs; D012604:Scorpion Venoms; D000675:Ampyrone; D004177:Dipyrone; D015232:Dinoprostone; C008667:noramidopyrine; D007213:Indomethacin
LPS; Tityus serrulatus venom; dipyrone; dipyrone metabolites; fever; hypothermia