Pharmacokinetics of metamizole (dipyrone) as an add-on in calves undergoing umbilical surgery

Abstract

This preliminary clinical investigation of the pharmacokinetic behavior of the main metamizole (dipyrone) metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) in calves undergoing umbilical surgery is part of an already published main study. A single intravenous dose of metamizole was added to ketamine/xylazine/isoflurane anesthesia. Eight Simmental calves weighing 90 ± 10.8 kg and aged 47.6 ± 10.4 days received 40 mg/kg metamizole intravenously 10 minutes prior to general anesthesia. Blood samples were collected over 24 hours and analyzed for 4-MAA and 4-AA. Meloxicam was additionally given twice: 2.5 hours pre- and 20.5 hours postsurgically. The pharmacokinetic profile of 4-MAA was best fitted to a two-compartment model and was characterized by a fast distribution half-life and slow elimination half-life (t½alpha = 5.29 minutes, t½beta = 9.49 hours). The maximum concentration (Cmax 101.63 μg/mL) was detected at the first measurement time point 15 minutes after administration. In contrast, 4-AA showed fast, high and biphasic plasma peak concentration behavior in five calves (2.54-2.66 μg/mL after 15-30 minutes, and 2.10-2.14 μg/mL after 2-3.5 hours) with a t½beta of 8.87 hours, indicating a rapid distribution and subsequent redistribution from well-perfused organs. Alternatively, three calves exhibited a slower and lower monophasic plasma peak concentration (1.66 μg/mL after 6.5 hours) with a t½beta of 6.23 hours, indicating slow accumulation in the intravascular compartment. The maximum concentration and area under the plasma concentration curve (AUC) of 4-AA were lower than those of 4-MAA. This metabolic behavior supports our already published data on clinical monitoring and plasma cortisol concentrations (PCCs). Compared to those of saline controls, lower PCCs correspond to the t½alpha of 4-MAA. Data on Tmax and t½beta also match these clinical observations. However, further studies are required to assess the exact analgesic mechanism and potency of the metamizole metabolites in calves.

Fig 1. Plasma concentration over time of 4-MAA after intravenous administration of 40 mg/kg metamizole in calves subjected to ketamine/xylazine/isoflurane anesthesia.

Values are the mean ± S.D. from n = 8 calves.

Fig 2

a. Plasma concentration over time of 4-AA after intravenous administration of 40 mg/kg metamizole in “fast metabolizing” calves subjected to ketamine/xylazine/isoflurane anesthesia. Values are the mean ± S.D. from n = 5 calves. b. Plasma concentration over time of 4-AA after intravenous administration of 40 mg/kg metamizole in “slow metabolizing” calves subjected to ketamine/xylazine/isoflurane anesthesia. Values are the mean ± S.D. from n = 3 calves.