Influence of Tramadol on the Intravenous Pharmacokinetics of Dipyrone Active Metabolites in Dogs

ABSTRACT This study aimed to compare the pharmacokinetic profile of the active dipyrone metabolites 4‐methylaminoantipyrine (MAA) and 4‐aminoantipyrine (AA) administered alone and in combination with tramadol in dogs. Nine mixed‐breed dogs, weighing 15.33 ± 2.25 kg, participated in a two‐treatment crossover design: G1 received intravenous dipyrone (25 mg kg −1 ) and G2 received dipyrone (25 mg kg −1 ) combined with tramadol (2 mg kg −1 ), with a 15‐day washout. Blood samples were collected up to 48 h and plasma concentrations analyzed using UPLC–MS/MS. Pharmacokinetic parameters were calculated using PKSolver 2.0. Normally distributed data were analyzed with the t ‐test, and non‐normal data with the Mann–Whitney test ( p < 0.05); parameters with significant differences were subjected to Pearson correlation. Analyses were performed using Python. For MAA, Cmax and C0 differed significantly. For AA, AUC 0– t , AUC 0→∞ , Cl, and MRT 0→∞ differed significantly. Tramadol and its metabolites were also described. The pharmacokinetic interaction between dipyrone and tramadol increased systemic exposure (AUC) of AA and inhibited the conversion of tramadol to M1, without direct changes in the severe adverse effects associated with MAA. Further studies involving nociceptive stimuli and multiple‐dose regimens are needed to assess clinical relevance.