Pharmacokinetic investigations of the marker active metabolite-4-methylamino-antipyrin after intravenous and intramuscular injection of metamizole in healthy sheep

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine, and dogs. MT is rapidly hydrolysed to the primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared to other minor metabolites, and it has been selected from the regulatory European Medicines Agency as a marker residue for MRL calculation. The aim of this research was to evaluate the pharmacokinetic profiles of MAA after 20mg/kg MT by intravenous (IV) and intramuscular (IM) administrations in healthy sheep. Twelve sheep were randomly allocated to two equal treatment groups according to a 2×2 crossover study. Blood was collected at predetermined times within 36h and plasma was analysed by a validated HPLC UV method. No behavioural changes or alterations in health parameters were observed in the IV or IM groups of animals during or after (up to 7 days) the drug administration. Plasma concentrations of MAA after IV administration of MT were detectable from 5min to 8h in all the sheep, they were still detectable at 10h in two animals, and the plasma quantification of MAA was possible from 5min to 10h in all the animals after IM administration. The only two significantly different parameters between the groups were maximum concentration (Cmax) and time to maximum concentration (Tmax) (P<0.01). The AUCIM/AUCIV was 1.12. The present study showed that no clinically relevant difference in the MAA was found after IM and IV administration of MT. Further studies are now necessary to assess the safety and efficacy profile of MT in sheep.