Pharmacokinetic profiles of the active metamizole metabolites in healthy horses

Abstract

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs. MT is rapidly hydrolysed to the active primary metabolite 4-methylaminoantipyrine (MAA). MAA is formed in much larger amounts compared with other minor metabolites. Among the other secondary metabolites, 4-aminoantipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.) and intramuscular (i.m.) routes in healthy horses. Six horses were randomly allocated to two equally sized treatment groups according to a 2 × 2 crossover study design. Blood was collected at predetermined times within 24 h, and plasma was analysed by a validated HPLC-UV method. No behavioural changes or alterations in health parameters were observed in the i.v. or i.m. groups of animals during or after (up to 7 days) drug administration. Plasma concentrations of MAA after i.v. and i.m. administrations of MT were detectable from 5 min to 10 h in all the horses. Plasma concentrations of AA were detectable in the same range of time, but in smaller amounts. Maximum concentration (C ), time to maximum concentration (T ) and AUMC of MAA were statistically different between the i.v. and i.m. groups. The AUC /AUC ratio of MAA was 1.06. In contrast, AUC of AA was statistically different between the groups (P < 0.05) with an AUC /AUC ratio of 0.54. This study suggested that the differences in the MAA and AA plasma concentrations found after i.m. and i.v. administrations of MT might have minor consequences on the pharmacodynamics of the drug.

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

“…A relatively similar AUC EV/i.v . ratio was found in a recent study in the dog (Giorgi et al., submitted), which used the same injection site, buttock muscle, as the present study, whereas, horses, sheep, and donkeys were injected in the neck muscle (Aupanun et al., ; Giorgi et al., , ). In general, the extent of systemic absorption of drugs injected intramuscularly is higher when the site of injection is the lateral neck compared to the buttock region, as this location provides a larger absorptive surface area with higher blood flow to tissues (Baggot, ).…”

“…The i.m.‐administered group showed the shortest elimination half‐life among the routes of administration. The present study showed markedly longer elimination half‐life in all administration routes than those previously reported for humans (4–5.5 hr), horses (4.2–6.4 hr), and donkeys (2.6–3.8 hr) with higher C max and AUC values (Aupanun et al., ; Giorgi et al., ; Vlahov et al., ). AA is known to be converted into AAA by a polymorphic N‐acetyltransferase (NAT2) enzyme (Geisslinger, Böcker, & Levy, ).…”

“…The elimination rate constant of MAA was similar in all administration routes with an elimination half‐life of about 6–7 hr, which was evidently longer than those from the sheep, horse, and donkey (about 1–3 hr) (Aupanun et al., ; Giorgi et al., , ). This might suggest relatively slow elimination of MAA itself or conversion of MAA to AA in cats.…”

“…and i.m. administrations in sheep, horses, and donkeys (Aupanun et al., ; Giorgi et al., , ). However, unlike the present study, the AUC values were comparable between i.v.‐ and i.m.‐administered groups in horses and sheep, indicating similar drug exposure in the body after both injectable administrations with high AUC EV/i.v .…”

“…However, unlike the present study, the AUC values were comparable between i.v.‐ and i.m.‐administered groups in horses and sheep, indicating similar drug exposure in the body after both injectable administrations with high AUC EV/i.v . ratio (1.06 and 1.12 for horse and sheep, respectively) (Giorgi et al., , ). Moreover, in donkeys, the AUC was even higher in the i.m.‐administered group when compared to the i.v.‐treated group with statistical significance (Aupanun et al., ).…”