Pharmacokinetic Profile of Two Active Dipyrone Metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), Following Intravenous Administration in Dogs: A Preliminary Study

TL;DR

This study examines how two active forms of dipyrone are processed in dogs' bodies after an injection, revealing differences in metabolism rates and effective pain-relief concentrations.

Contribution

The study provides the first UPLC-MS/MS-based pharmacokinetic analysis of dipyrone metabolites in dogs and identifies variable metabolism rates.

Findings

Dipyrone metabolites reached minimum effective concentrations for analgesia in dogs.

Two groups of metabolizers (fast and slow) were identified for MAA using PCA.

Metabolites remained detectable for up to 48 hours in all dogs for MAA and seven for AA.

Abstract

Dipyrone is widely used to control pain. However, although the standard dose for routine use is 25 mg·kg−1, no studies addressing the pharmacokinetics of this drug employing ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS/MS) are available to date. Thus, the aim of this study was to determine the pharmacokinetic profile of the active metabolites of dipyrone 4-methylaminoantipyrine (MAA) and 4-aminoantipyrine (AA) administered intravenously, at 25 mg·kg−1, in eleven mixed-breed dogs (weighing 14.43 ± 2.86 kg). Serial blood samples were collected after the drug administration, stored at −80 °C and analyzed by high-performance chromatography coupled to mass spectrometry. A Principal Component Analysis (PCA) indicated two groups of metabolizers, fast and slow, for MAA. This demonstrates metabolism variability within the same group of mixed-breed dogs. Furthermore, the minimum effective concentrations for promoting analgesia in humans were reached for dipyrone metabolites. These results suggest that dipyrone achieves therapeutic plasma concentration with minimal adverse effects. However, further pharmacogenetic and pharmacotherapeutic studies are required to refine dosing recommendations.

This study aimed to determine the pharmacokinetic profile of the active dipyrone metabolites, 4-methylaminoantipyrine and 4-aminoantipyrine, following intravenous administration in dogs. Eleven mixed-breed dogs received a 25 mg·kg−1 dipyrone dose and blood samples were collected at 0, 5, 15, 30 and 45 min, as well as at 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 36 and 48 h. Plasma concentrations of both metabolites were analyzed by ultra-performance liquid chromatography coupled to mass spectrometry. The PKSolver 2.0 and GraphPad Prisma 10 software programs were used for pharmacokinetic and statistical analyses, applying a Principal Component Analysis for MAA and descriptive statistics for both metabolites. Two groups were noteworthy concerning MAA: slow metabolizers (SM) and normal/rapid metabolizers (NM). Significant differences were observed between half-life (T½) and MRT0_inf obs values between the MAA groups. The T½ and MRT0_info obs were 44.44 ± 11.74 and 32.62 ± 16.53 h for the SM group and 11.25 ± 5.37 and 7.44 ± 4.25 h for the NM group, respectively. The Cmax of AA was 2.80 ± 1.43 µg mL−1. Metabolites were detectable for 48 h in all animals for MAA and seven for AA. These findings suggest that metamizole reaches analgesia plasma concentrations associated with cyclooxygenase inhibition with few adverse effects in dogs. However, additional pharmacogenetic and pharmacotherapeutic monitoring studies are required.

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