title: Pharmacokinetics and pharmacodynamics of metamizol in co-administration with morphine under acute and chronic treatments in arthritic rats.
abstract: OBJECTIVE
  To investigate the relationship between metamizol pharmacokinetics and the antinociceptive effect produced after subcutaneous administration of metamizol (177.8 mg/kg) alone or in combination with morphine (3.2 mg/kg), under acute and chronic treatments.
  
  
  METHODS
  Antinociception was assessed using the pain-induced functional impairment model in rat (PIFIR). Serial blood samples were collected from the same animals to study the pharmacokinetics of metamizol.
  
  
  RESULTS
  The co-administration of the drugs in single dose, confirmed the potentiation of their individual antinociceptive effects. When the drugs were administered alone following the chronic schedule, a pronounced tolerance development to their antinociceptive effects was found, whereas it was significantly attenuated when they were administered together. Metamizol pharmacokinetics was unaltered by the presence of morphine. Plasma concentrations of 4-methylaminoantipyrine, an active metabolite markedly decreased under chronic administration.
  
  
  CONCLUSIONS
  The mechanism involved in the potentiation of the antinociceptive effect produced by the combination, cannot be explained by the interaction of morphine on metamizol pharmacokinetics. Other pharmacokinetic interactions along with known pharmacodynamic interactions in which metamizol active metabolites contribute, should be considered. The frequency of administration enhances tolerance development and induces metamizol elimination process.
authors.affiliation: Maestría en Ciencias Farmacéuticas, Universidad Autónoma Metropolitana, Unidad Xochimilco, México, México.
authors.forename: Patricia Esmeralda
authors.initials: PE
authors.lastname: Carrillo-Calzadilla
authors.affiliation: Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados, México, México.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: López-Muñoz
authors.affiliation: Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, México City, México.
authors.forename: Luis Alfonso
authors.initials: LA
authors.lastname: Moreno-Rocha
authors.affiliation: Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, México City, México.
authors.forename: José Raúl
authors.initials: JR
authors.lastname: Medina-López
authors.affiliation: Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, México City, México.
authors.forename: Alma Rosa
authors.initials: AR
authors.lastname: Cortés-Arroyo
authors.affiliation: Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana Unidad Xochimilco, México City, México.
authors.forename: Adriana Miriam
authors.initials: AM
authors.lastname: Domínguez-Ramírez
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004177:Dipyrone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D004361:Drug Tolerance; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D004177:Dipyrone; D009020:Morphine
keywords: metamizol; morphine; pharmacodynamics; pharmacokinetics; tolerance