Research Article Antinociceptive Activity of Metamizol Metabolites in a Rat Model of Arthritic Pain Francisco Javier López-Muñoz, 1 Olivia Soria-Arteche, 2 José Raúl Medina López, 2 Marcela Hurtado y de la Peña, 2 Ma. Concepción Lozada García, 2 Luis Alfonso Moreno-Rocha, 2 and Adriana Miriam Domínguez-Ramírez 2 * 1 Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados, Sede Sur, Colonia Granjas Coapa, México, D.F., C.P. 14330, México 2 Departamento Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Colonia Villa Quietud, México, D.F., C.P. 04960, México Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I-III Regulatory, Quality, Manufacturing Postmarketing Phase IV ABSTRACT The aim of the present study was to evaluate the antinociceptive activity of the main metami- zol (MET) metabolites, 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA), and 4-acetylaminoantipyrine (AAA) using the “pain-induced functional impairment in rat” model (PIFIR model).The antinociceptive efficacies of MAA and AA were 288.3% h and 281.1% h, respectively, close to the efficacy of MET (333.80% h). The effective dose to attain 50% of the maximum response (ED50) values for MET, MAA and AA were 126.1, 124.9, and 110.7 mg/kg, respectively. FAA and AAA were essentially inactive in this experimental model. Part of the antinociceptive effect showed by MET in this study might be attributed to the effect of the metabolites MAA and AA on cyclooxygenases COX-1 and COX-2 activity. Drug Dev Res •• : ••–••, 2013. © 2013 Wiley Periodicals, Inc. Key words: metamizol; metabolites; synthesis; antinociception; PIFIR model INTRODUCTION Metamizol (MET) is a nonsteroidal anti- inflammatory pro-drug that is an effective analgesic, antipyretic, and antispasmodic agent. Initially, MET was classified as a peripherally acting drug as its major metabolites act as cyclooxygenase (COX) inhibitors [Brune and Alpermann, 1983; Brogden, 1986]. How- ever, MET is much more effective as an antipyretic and analgesic drug than as anti-inflammatory agent in vivo, thus it has been proposed that MET inhibits prostaglan- din synthesis centrally but not peripherally [Campos et al., 1999] and that its antinociceptive effect is medi- ated by central mechanisms [Carlsson et al., 1986; Tortorici et al., 1996]. Other authors have suggested that COX-2 through its peroxidase function, is the target [Aronoff et al., 2006] or that another variant of COX-1, the putative COX-3 located in the central nervous system (CNS), is the enzyme inhibited by MET [Chandrasekharan et al., 2002] although the relevance Funding/support: This study was partially supported by grants from CONACYT (Project 53231) and SEP-PIFI 3.3 (UAM-X-CA-29). Conflict of interest: The authors declare that they have no conflict of interest to disclose. *Correspondence to: Adriana Miriam Domínguez-Ramírez, Departamento Sistemas Biológicos, Universidad Autónoma Metropolitana-Unidad Xochimilco, Calzada del Hueso 1100, ColoniaVilla Quietud, México, D.F., C.P. 04960, México. E-mail: adoming@correo.xoc.uam.mx Received 15 March 2013; Accepted 16 April 2013 Published online in Wiley Online Library (wileyonlinelibrary. com). DOI: 10.1002/ddr.21083 DRUG DEVELOPMENT RESEARCH •• : ••–•• (2013) DDR © 2013 Wiley Periodicals, Inc.