Pharmacokinetic profiles of the two major active metabolites of metamizole (dipyrone) in cats following three different routes of administration

Abstract

This study was performed to determine pharmacokinetic profiles of the two active metabolites of the analgesic drug metamizole (dipyrone, MET), 4-methylaminoantipyrine (MAA), and 4-aminoantipyrine (AA), after intravenous (i.v., intramuscular (i.m.), and oral (p.o.) administration in cats. Six healthy mixed-breed cats were administered MET (25 mg/kg) by i.v., i.m., or p.o. routes in a crossover design. Adverse clinical signs, namely salivation and vomiting, were detected in all groups (i.v. 67%, i.m. 34%, and p.o. 15%). The mean maximal plasma concentration of MAA for i.v., i.m., and p.o. administrations was 148.63 ± 106.64, 18.74 ± 4.97, and 20.59 ± 15.29 μg/ml, respectively, with about 7 hr of half-life in all routes. Among the administration routes, the area under the plasma concentration curve (AUC) value was the lowest after i.m. administration and the AUC . ratio was higher in p.o. than the i.m. administration without statistical significance. The plasma concentration of AA was detectable up to 24 hr, and the mean plasma concentrations were smaller than MAA. The present results suggest that MET is converted into the active metabolites in cats as in humans. Further pharmacodynamics and safety studies should be performed before any clinical use.

Pharmacokinetic profiles of metamizole (dipyrone) active metabolites in goats and its residues in milk

“…The rapid MET conversion might be due to the direct introduction of parent drug into the systemic circulation where an absorption phase can be omitted. This finding is in line with other studies (Aupanun et al., , Giorgi et al., ; Giorgi, Aupanun, et al., ; Giorgi, Łebkowska‐Wieruszewska, et al., ; Lebkowska‐Wieruszewska et al., ). Meanwhile, as expected, IM administration showed a relatively delayed C max for MAA when compared to the IV administration.…”

“…Metamizole is a prodrug known to rapidly decrease in concentration and transform into its active metabolites in humans after IV administration (Levy et al., ). Due to the rapid metabolism of MET, MAA and AA are used as markers for the study of MET pharmacokinetics (Giorgi, Aupanun, et al., ; Giorgi, Łebkowska‐Wieruszewska, et al., ; Lebkowska‐Wieruszewska et al., ; Levy et al., ).…”

“…Although no relevant adverse effects have been reported for MET in several animal species including cattle and horses for several years, the use of drugs in food‐producing animals needs particular caution because of the potential for residues, improper use of drugs is the major source of drug residues found in milk (EMEA report, ). In recent times, there has been an increase in studies reporting the pharmacokinetics of MET in veterinary species (Aupanun et al., ; Giorgi et al., ; Giorgi, Aupanun, et al., ; Giorgi, Łebkowska‐Wieruszewska, et al., ; Lebkowska‐Wieruszewska et al., ). To the best of the authors’ knowledge, the pharmacokinetics of two active metabolites of MET in the goat has not been reported yet.…”

Pharmacokinetic profiles of the active metamizole metabolites after four different routes of administration in healthy dogs

“…In contrast, the evidence is not as strong in veterinary medicine. Some data regarding clinical and side effects of MT in horses, rabbits, rats, and dogs have been reported, and there is addition data in relation to the pharmacokinetic profile of the metabolite MAA in horses, donkeys, pigs, rats, dogs, cats, and sheep (Aupanun et al., ; Baumgartner et al., ; Burmańczuk et al., ; Christ, Kellner, Ross, Rupp, & Schwarz, ; Flôr, Yazbek, Ida, & Fantoni, ; Giorgi et al., , ; Imagawa et al., ; Klaus, Schlingloff, Kleinitz, Böttcher, & Hapke, ; Lebkowska‐Wieruszewska et al., ; Loescher, ; Roelvink, Goossens, Kalsbeek, & Wensing, ; Silva‐Moreno, Lopez‐Munoz, & Cruz, ; Teixeira et al., ; Zanuzzo et al., ).…”

“…The panel focus on the relevant area of the curve where the IC50s (-) for the human COX enzymes are located F I G U R E 4 Mean plasma concentrations of 4-aminoantypyrine (AA) vs. time curves following intravenous ( ), intramuscular ( ), oral ( ), and rectal ( ) dose of 25 mg⁄kg metamizole (MT) in healthy dogs (n = 6). Bars represent the standard deviations ,& Schwarz, 1973;Flôr, Yazbek, Ida, & Fantoni, 2013;Giorgi et al, 2015Giorgi et al, , 2017Imagawa et al, 2011;Klaus, Schlingloff, Kleinitz, Böttcher, & Hapke, 1997;Lebkowska-Wieruszewska et al, 2017;Loescher, 1993;Roelvink, Goossens, Kalsbeek, & Wensing, 1991;Silva-Moreno, Lopez-Munoz, & Cruz, 2009;Teixeira et al, 2013;Zanuzzo et al, 2015).Due to MT's striking pharmacological effect, low cost and safety profile, there has been growing interest in its use in the veterinary field over the past decade. Although MT is widely used in clinical practice, pharmacokinetic-pharmacodynamic profiles of MT or its active metabolites are limited or absent.…”