Pharmacokinetic Profiles of the Two Major Active Metabolites of Metamizole, 4-Methylaminoantipyrine (Maa) and 4-Aminoantipyrine (Aa), after Intravenous Injection in Cats

Abstract

This study aimed to determine the pharmacokinetic profile of two active metabolites of metamizole (dipyrone), N-methyl-4-aminoanthypyrine and 4-aminoanthypyrine, after intravenous administration in cats. Eight healthy mixed-breed cats were intravenously administered metamizole (25 mg/kg). Blood samples were collected at predetermined time points for up to 48 h after administration. Information on behavioral changes in the animals and adverse effects was collected. Plasma aliquots were processed and analyzed using the ultra-performance liquid chromatography tandem mass spectrometry technique. Salivation was identified as an adverse clinical sign. The mean maximal plasma concentrations of N-methyl-4-aminoanthypyrine and 4-aminoanthypyrine were 29.31 ± 24.57 μg/mL and 1.69 ± 0.36 μg/mL, with half-lives of around 4.98 and 14 hr, respectively. The area under the plasma concentration curve values were 28.54 ± 11.33 and 49.54 ± 11.38 h*µg/mL for N-methyl-4-aminoanthypyrine and 4-aminoanthypyrine, respectively. The plasma concentration of N-methyl-4-aminoanthypyrine was detectable for up to 24 h and was smaller than 4-aminoanthypyrine. 4-aminoanthypyrine was detectable for more than 48 h. Results suggest that metamizole is converted into active metabolites in cats, similar to findings in humans. A validated UPLC-MS/MS method was used to characterize the pharmacokinetics of N-methyl-4-aminoanthypyrine and 4-aminoanthypyrine. Further PK/PD and safety studies should be performed before defining the dose or administration intervals for clinical use.

Keywords: Analgesics, Dipyrone, feline, N-methyl-4-aminoantipyrine, 4-aminoantipyrine