Data Metamizole Pharmacokinetics Mice

Data concerning the following project/manuscript:

Pharmacokinetics, efficacy, and safety of metamizole in C57BL/6J mice after subcutaneous injection and during voluntary oral self-intake

Background
Metamizole is a widely used analgesic in both human and veterinary medicine with analgesic, antipyretic, and spasmolytic properties and is also commonly utilized in laboratory animal research. Nevertheless, pharmacokinetics of metamizole in mice has not been described yet and information on efficacy and tolerability are rare. Acquisition of these data would contribute to optimization in pain management and therefore to refinement of pain-associated interventions according to the 3R principles.
Results
Pharmacokinetics, antinociceptive efficacy, and tolerability of metamizole in healthy male and female C57BL/6J mice were investigated after single s.c. injection (50 mg/kg) and during oral self-administration via drinking water (200 mg/kg/24 h over 5 days). Additionally, the potential influence of metamizole on established behavioral parameters for pain assessment was determined. Plasma elimination half-life was 0.91 h for metamizole metabolite 4-methylaminoantipyrine and 1.72 h for 4-aminoantipyrine after s.c. injection. Simulated repeated injection analysis suggests injection intervals of 2 h or less to achieve stable plasma levels. During oral self-administration, metamizole-medicated water was voluntarily consumed, resulting in target dose intake. Plasma levels reached maximum within the first 12 h and remained stable at relatively low levels between 36 and 120 h during oral administration. The hot water tail immersion test did not indicate an antinociceptive effect of metamizole, but a correlation between 4-methylaminoantipyrine plasma levels and latency to tail withdrawal after s.c. injection was found. In general, metamizole was well tolerated at both administration routes, without changes in body weight, clinical score, or body temperature. However, tolerability assessment revealed influence on excitation, coordination, and sedation, and some minor effects on hematological parameters and histology of the stomach. The most part of behavioral parameters were unaffected, except early nesting and wheel running activity, particularly in male mice.
Conclusions
This study provides novel insights into pharmacokinetics, antinociceptive efficacy, and tolerability of metamizole in C57BL/6J mice. While metamizole was overall well tolerated and voluntarily consumed, antinociceptive efficacy at the investigated doses was limited. The short half-life of the metabolites implies limited use as analgesic in mice, therefore further research on dose optimization and therapeutic plasma levels is required to assess the suitability of metamizole for pain management.