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We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>Male W<\/jats:styled-content>istar rats were treated i.p. with indomethacin (2\u2009mg\u00b7kg\u22121<\/jats:sup>), dipyrone, 4\u2010methylaminoantipyrine (4\u2010MAA<\/jats:styled-content>), 4\u2010aminoantipyrine (4\u2010AA<\/jats:styled-content>) (60\u2013360\u2009mg\u00b7kg\u22121<\/jats:sup>), 4\u2010formylaminoantipyrine, 4\u2010acethylaminoantipyrine (120\u2013360\u2009mg\u00b7kg\u22121<\/jats:sup>) or vehicle 30\u2009min before i.p. injection of LPS<\/jats:styled-content> (50\u2009\u03bcg\u00b7kg\u22121<\/jats:sup>), T<\/jats:styled-content>sv (150\u2009\u03bcg\u00b7kg\u22121<\/jats:sup>) or saline. Rectal temperatures were measured by tele\u2010thermometry and dipyrone metabolite concentrations determined in the plasma, CSF<\/jats:styled-content> and hypothalamus by LC<\/jats:styled-content>\u2010MS\/MS<\/jats:styled-content>. PGE<\/jats:styled-content>2<\/jats:sub> concentrations were determined in the CSF<\/jats:styled-content> and hypothalamus by elisa<\/jats:sc>.<\/jats:p><\/jats:sec>Key Results<\/jats:title>In contrast to LPS<\/jats:styled-content>, T<\/jats:styled-content>sv\u2010induced fever was not followed by increased PGE<\/jats:styled-content>2<\/jats:sub> in the CSF<\/jats:styled-content> or hypothalamus. The antipyretic time\u2010course of 4\u2010MAA<\/jats:styled-content> and 4\u2010AA<\/jats:styled-content> on LPS<\/jats:styled-content>\u2010induced fever overlapped with the period of the highest concentrations of 4\u2010MAA<\/jats:styled-content> and 4\u2010AA<\/jats:styled-content> in the hypothalamus, CSF<\/jats:styled-content> and plasma. These metabolites reduced LPS<\/jats:styled-content>\u2010induced fever and the PGE<\/jats:styled-content>2<\/jats:sub> increase in the plasma, CSF<\/jats:styled-content> and hypothalamus. Only 4\u2010MAA<\/jats:styled-content> inhibited T<\/jats:styled-content>sv\u2010induced fever. The higher doses of dipyrone and 4\u2010MAA<\/jats:styled-content> also induced hypothermia.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>The presence of 4\u2010MAA<\/jats:styled-content> and 4\u2010AA<\/jats:styled-content> in the CSF<\/jats:styled-content> and hypothalamus was associated with PGE<\/jats:styled-content>2<\/jats:sub> synthesis inhibition and a decrease in LPS<\/jats:styled-content>\u2010induced fever. 4\u2010MAA<\/jats:styled-content> was also shown to be an antipyretic metabolite for PGE<\/jats:styled-content>2<\/jats:sub>\u2010independent fever induced by T<\/jats:styled-content>sv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4\u2010MAA<\/jats:styled-content> is the hypothermic metabolite of dipyrone.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12717","type":"journal-article","created":{"date-parts":[[2014,4,8]],"date-time":"2014-04-08T11:11:44Z","timestamp":1396955504000},"page":"3666-3679","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Dipyrone metabolite 4\u2010MAA<\/scp> induces hypothermia and inhibits PGE<\/scp>2<\/sub>\u2010dependent and \u2010independent fever while 4\u2010AA<\/scp> only blocks PGE<\/scp>2<\/sub>\u2010dependent fever"],"prefix":"10.1111","volume":"171","author":[{"given":"David do C","family":"Malvar","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando A","family":"Aguiar","sequence":"additional","affiliation":[{"name":"N\u00facleo de Pesquisa em Produtos Naturais e Sint\u00e9ticos Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artur de L L","family":"Vaz","sequence":"additional","affiliation":[{"name":"N\u00facleo de Pesquisa em Produtos Naturais e Sint\u00e9ticos Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D\u00e9bora C R","family":"Assis","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo 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