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The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug-drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450-mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma-hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5-OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5-OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug-drug interactions and identification of reasons for varying pharmacokinetics between horses.

BACKGROUND: Flunixin meglumine (FM) was investigated for the effectiveness of plasma, oral fluid, and urine concentrations to predict tissue residue depletion profiles in finishing-age swine, along with the potential for untreated pigs to acquire tissue residues following commingled housing with FM-treated pigs. Twenty pigs were housed in groups of three treated and one untreated control. Treated pigs received one 2.2 mg/kg dose of FM intramuscularly. Before treatment and at 1, 3, 6, 12, 24, 36, and 48 h (h) after treatment, plasma samples were taken. At 1, 4, 8, 12 and 16 days (d) post-treatment, necropsy and collection of plasma, urine, oral fluid, muscle, liver, kidney, and injection site samples took place. Analysis of flunixin concentrations using liquid chromatography/tandem mass spectrometry was done. A published physiologically based pharmacokinetic (PBPK) model for flunixin in cattle was extrapolated to swine to simulate the measured data.RESULTS: Plasma concentrations of flunixin were the highest at 1 h post-treatment, ranging from 1534 to 7040 ng/mL, and were less than limit of quantification (LOQ) of 5 ng/mL in all samples on Day 4. Flunixin was detected in the liver and kidney only on Day 1, but was not found 4-16 d post-treatment. Flunixin was either not seen or found less than LOQ in the muscle, with the exception of one sample on Day 16 at a level close to LOQ. Flunixin was found in the urine of untreated pigs after commingled housing with FM-treated pigs. The PBPK model adequately correlated plasma, oral fluid and urine concentrations of flunixin with residue depletion profiles in liver, kidney, and muscle of finishing-age pigs, especially within 24 h after dosing.CONCLUSIONS: Results indicate untreated pigs can be exposed to flunixin by shared housing with FM-treated pigs due to environmental contamination. Plasma and urine samples may serve as less invasive and more easily accessible biological matrices to predict tissue residue s

Introduction: The study objectives were to estimate plasma flunixin (FLU) pharmacokinetic parameters and milk depletion profiles for FLU and its metabolite (5-hydroxy flunixin; 5-OH) after subcutaneous (SC) and intravenous (IV) administration of single and multiple flunixin meglumine (FM) doses to non-lactating (nulliparous and pregnant does) and lactating dairy goats. Analytical methods (ELISA and UPLC-MS/MS) for quantifying plasma FLU concentrations were compared. The final objective was to use regulatory (FDA and EMA) methods to estimate milk withdrawal intervals following extra-label drug use in goats. Methods: FM was administered IV and SC to commercial dairy goats at 1.1 mg/kg for single and multiple doses. Plasma and milk samples were analyzed for FLU and 5-OH via UPLC-MS/MS. Plasma samples were also analyzed for FLU concentrations via ELISA. Using statistical approaches recommended by regulatory agencies, milk withdrawal intervals were estimated following FM extra-label use. Results: Following IV administration of a single FM dose, clearances were 127, 199, and 365 ml/kg/h for non-lactating (NL) pregnant does, NL nulliparous does, and lactating dairy does, respectively. Following multiple SC doses, clearance/F was 199 ml/kg/h for lactating does. After IV administration of a single FM dose, terminal elimination half-lives were 4.08, 2.87, and 3.77 h for NL pregnant does, NL nulliparous does, and lactating dairy does, respectively. After multiple SC doses, the terminal elimination half-life was 3.03 h for lactating dairy does. No significant differences were noted for samples analyzed by UPLC-MS/MS or ELISA. Milk withdrawal intervals ranged from 36 to 60 h depending on the regulatory statistical method and dosage regimen. Conclusions: Subcutaneous administration of FM to goats results in similar plasma pharmacokinetic parameters as IV administration. ELISA analysis is an alternative method to UPLC-MS/MS for quantifying FLU concentrations in caprine plasma samp

This study investigated whether the L-arginine-NO system participates in the analgesic effect of flunixin meglumine in the rat. Hyperalgesia was induced by intraplantar (i.pl.) administration of carrageenan (500 μg) into the rat's hind paw. Electronic von Frey apparatus was used to determine paw withdrawal threshold induced by pressure as the painful stimulus, measured in grams (g). Flunixin meglumine (FM; 0.09-0.1 mg/kg; s.c.) and NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg; i.p.), given separately as a pre-treatment, i.e. 15 min before i.pl. injection of carrageenan, produced a significant antinociception. When FM (0.09 mg/kg) and a sub-effective dose of L-NAME (5 mg/kg) were co-administered, the antinociceptive effect was significantly increased in comparison with the effect of FM alone. L-arginine (L-ARG;10 mg/kg; i.p.) itself did not produce significant effect on carrageenan-induced hyperalgesia, but significantly reduced the antinociceptive effects of both FM and FM + L-NAME combination. The inhibition of the production of NO might be involved in the mechanism of the analgesic effect of FM., Ova studija ispituje da li L-arginin-NO sistem učestvuju u analgetskom dejstvu fluniksin meglumina kod pacova. Hiperalgezija je izazvana intraplantarnom (i.pl.) aplikacijom karagenina (500 μg) u zadnju šapu pacova. Elektronski von Frey aparat se koristi za određivanje praga osetljivosti šape izazvane pritiskom kao bolnim stimulusom, i meri se u gramima (g). Fluniksin meglumin (FM; 0,09-0,1 mg/kg, s.c.) i NG-nitro-L-arginin metil estar (L-NAME; 10 mg/kg, i.p.), dati odvojeno u pretretmanu, tj. 15 min pre i.pl. aplikacije karagenina, prouzrokuju značajnu antinocicepciju. Kada se FM (0,09 mg/ kg) i L-NAME u sub-efektivnoj dozi (5 mg/kg) primene zajedno, antinociceptivni efekat se značajno povećava u odnosu na efekat primene samog FM. L-arginin (10 mg/ kg; i.p.) sam ne deluje na hiperalgeziju izazvanu karageninom, ali značajno smanjuje antinociceptivno dejstvo FM i kombinacije FM + L-NAME. Inhibicija produkcije NO-a može biti uključena u mehanizam analgetičkog efekta FM.

The aim of the 21 day toxicity study was to evaluate the pathomorphological effect of flunixin meglumine in layer chicks. The chicks of Group I were kept as control while groups II, III and IV were fed with diet containing flunixin meglumine @ 10 ppm, 25 ppm and 50 ppm respectively for 21 days. Clinical signs viz. anorexia, dullness,lethargy, lameness and uneven growth were noticed in chicks of treatment groups III and IV only. Maximum mortality was observed in group IV (12%) followed by group III (4%). A dose dependant reduction in body weight was observed in all the treatment groups. The mean values of Kidney: Body weight ratio was significantly increased in group IV. The plasma uric acid, creatinine and BUN values were significantly increased in group III whereas increase in group IV was highly significant. Grossly, there was deposition of chalky white urates on serosal surface of kidney, heart and liver in chicks of group IV which died during experiment. Microscopically, lesions were characterized by varying degrees of congestion, haemorrhages, degeneration, necrosis and deposition of urate crystals in visceral organs of group III and group IV chicks. The intensity and distribution of pathological lesions were more severe in chicks of group IV, followed by chicks of group III. The overall lesions gave an impression that flunixin meglumine was nephrotoxic in nature.

Feral does of various ages were treated with intravaginal progestagen sponges for 16 days to synchronize oestrus. On Day 2 before sponge removal the goats were given 1200 i.u. PMSG to induce superovulation: 6 of the goats were also injected every 12 h with flunixin meglumine, a prostaglandin (PG) synthetase inhibitor, from Day 3 to 7 of the synchronized oestrous cycle. Jugular blood samples were collected from all females into heparinized syringes at daily intervals over the 2 days before sponge removal, twice daily for the next 2 days, then at hourly intervals from 09:00 to 17:00 h for 2 days and then twice daily for a further 2 days, for measurement of plasma progesterone and the PGF metabolite 13,14-dihydro-15-keto-PGF (PGFM) by radioimmunoassay. Intermittent surges in plasma PGFM concentrations were observed in hourly samples collected from 4/4 untreated females but in only 2/6 of the inhibitor-treated females (P < 0.05), and the peak plasma PGFM concentrations were reduced in these 2 inhibitor-treated goats compared with the control goats. The corpora lutea (CL) of the inhibitor-treated females appeared to be functional as indicated by the plasma progesterone profile and endoscopic examination of CL. In the control females, however, there was evidence of premature regression of CL. These results suggest that the premature release of PGF-2alpha may be the cause of premature regression of CL in nanny goats induced to superovulate.

During early lactation dairy cows often experience health disorders, which are usually associated with decreased production and reproduction variables. Following parturition, cows use more energy for maintenance and milk production than they consume and enter into a state of negative energy balance. Negative energy balance in early lactation is thought to contribute to decreased milk production, reduced reproductive performance, and increased health disorders. Flunixin meglumine (FM) is an anti-pyretic (fever reducing) and anti-inflammatory drug that is commonly used in the dairy industry. This study evaluated the effect of FM on pyrexia, production and bioenergetic variables in postparturient dairy cows.

During early lactation dairy cows often experience health disorders, which are usually associated with decreased production and reproduction variables. Following parturition, cows use more energy for maintenance and milk production than they consume and enter into a state of negative energy balance. Negative energy balance in early lactation is thought to contribute to decreased milk production, reduced reproductive performance, and increased health disorders. Flunixin meglumine (FM) is an anti-pyretic (fever reducing) and anti-inflammatory drug that is commonly used in the dairy industry. This study evaluated the effect of FM on pyrexia, production and bioenergetic variables in postparturient dairy cows.

The objectives of this study were to evaluate the effects of flunixin meglumine (FM), an inhibitor of PGF2a synthesis, administered at the time of embryo transfer (ET) and insertion of an intravaginal progesterone-releasing device (CIDR) at the time of ET on pregnancy rates (PR) and the resynchronization of estrus. Beef cows (n = 796) and heifers (n = 108) at three locations were assigned randomly within age to one of four groups in a 2 x 2 factorial arrangement of treatments with injection of FM (500 mg i.m.; Phoenix Scientific, St. Joseph, MO) 2 to 12 min prior to ET and insertion of a CIDR (1.38 g progesterone; Pfizer, New York, NY) for 13 d immediately following ET as main effects. Fresh or frozen embryos (Stage = 4 or 5; Grade = 1 or 2) were randomly assigned to be transferred to recipients on d 6 to 9 of the estrous cycle. At Location 2 a subset of fresh embryos were split and transferred as fresh half embryos (n = 192). Recipients at Location 2 only (n = 493) were observed for signs of return to estrus beginning 9 d after ET. Recipients that returned to estrus at Location 2 were either bred by AI 12 h after estrus or received an embryo 7 d after estrus. Pregnancy was diagnosed by ultrasonography. Pregnancy rates were analyzed using the LOGISTIC procedure of SAS. Pregnancy rates of split embryo recipients were analyzed separately using the same statistical procedure. Variation in the timing of the return to estrus was determined by an F-test for heterogeneity of variances. Following the initial ET, pregnancy rates of recipients receiving whole embryos were not affected by CIDR administration (P > 0.05; 65% with CIDR, 70% without CIDR), however, there was a significant FM x location interaction on PR (Location 1, 89 vs. 57%; Location 2, 69 vs. 64%; Location 3, 64 vs. 67% for FM vs. no FM, respectively). There was a significant CIDR x FM interaction on PR of recipients receiving split embryos. Pregnancy rates of split embryo recipients receiving CIDR treatment (