Antinociceptive Activity of Metamizol Metabolites in a Rat Model of Arthritic Pain

López‐Muñoz, Francisco; Soria‐Arteche, Olivia; López, José Raúl Medina; Peña, Marcela Hurtado y de la; García, Ma. Concepción Lozada; Moreno-Rocha, Luis Alfonso; Domínguez-Ramírez, Adriana Miriam

doi:10.1002/ddr.21083

Cited by 1 publication

(3 citation statements)

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“…Although no statistical differences were found for MAA pharmacokinetics, between MET and MET-4D schedules, in the case of AA metabolite, which is formed by oxidation of MAA, via CYP2D6 system, the areas under the curve decreased significantly ( P < 0.05), even when the decrease in β or half-life time, was not statistically significant ( P > 0.05). This may partly explain the decrease in the effect of metamizol in chronic treatment since it is known that AA shows a similar antinociceptive activity to that of MAA (López-Muñoz et al, 2013b).…”

Section: Discussionmentioning

confidence: 97%

“…Several explanations have been proposed for this performance, including the formation of active metabolites, or an effect compartment different from those detected by conventional pharmacokinetic analysis (Remington and Gennaro, 2006, Louizos et al, 2014). The possibility of active metabolites formation cannot be discarded since the AA metabolite that is formed from MAA, also shows a high pharmacological activity (López-Muñoz et al,, 2013b). On the other hand, the relationship between functionality index (FI%) and metabolite plasma concentration shown by metamizol plus tramadol combination groups, showed a clockwise hysteresis loop that may be the result of tolerance development by the presence of antagonistic metabolites that are formed as the drug is metabolized, or down-regulation of receptors and feedback regulation (Kwon, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…AA is acetylated to 4-acetylaminoantipyrine (AAA). MAA and AA produce a dose-dependent antinociceptive effect in arthritic rats (PIFIR model), whereas the other metabolites are inactive (López-Muñoz et al, 2013b).…”

Section: Introductionmentioning

confidence: 99%

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Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats

Moreno-Rocha

López‐Muñoz

López

et al. 2016

Saudi Pharmaceutical Journal

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Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively) is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone ( < 0.05). Nevertheless, this effect decreased about 53% after the chronic treatment (3 doses per day, for 4 days). No pharmacokinetic interaction between metamizol and tramadol was found under acute treatment ( > 0.05). The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites' pharmacokinetics ( < 0.05) were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%