Plasma, urine and tissue concentrations of Flunixin and Meloxicam in Pigs.

BACKGROUND: The objective of this study was to determine the renal clearance of flunixin and meloxicam in pigs and compare plasma and urine concentrations and tissue residues. Urine clearance is important for livestock show animals where urine is routinely tested for these drugs. Fourteen Yorkshire/Landrace cross pigs were housed in individual metabolism cages to facilitate urine collection. This is a unique feature of this study compared to other reports. Animals received either 2.2 mg/kg flunixin or 0.4 mg/kg meloxicam via intramuscular injection and samples analyzed by mass spectrometry. Pigs were euthanized when drugs were no longer detected in urine and liver and kidneys were collected to quantify residues. RESULTS: Drug levels in urine reached peak concentrations between 4 and 8 h post-dose for both flunixin and meloxicam. Flunixin urine concentrations were higher than maximum levels in plasma. Urine concentrations for flunixin and meloxicam were last detected above the limit of quantification at 120 h and 48 h, respectively. The renal clearance of flunixin and meloxicam was 4.72 ± 2.98 mL/h/kg and 0.16 ± 0.04 mL/h/kg, respectively. Mean apparent elimination half-life in plasma was 5.00 ± 1.89 h and 3.22 ± 1.52 h for flunixin and meloxicam, respectively. Six of seven pigs had detectable liver concentrations of flunixin (range 0.0001-0.0012 µg/g) following negative urine samples at 96 and 168 h, however all samples at 168 h were below the FDA tolerance level (0.03 µg/g). Meloxicam was detected in a single liver sample (0.0054 µg/g) at 72 h but was below the EU MRL (0.065 µg/g). CONCLUSIONS: These data suggest that pigs given a single intramuscular dose of meloxicam at 0.4 mg/kg or flunixin at 2.2 mg/kg are likely to have detectable levels of the parent drug in urine up to 2 days and 5 days, respectively, after the first dose, but unlikely to have tissue residues above the US FDA tolerance or EU MRL following negative urine testing. This information will assist veterinarians in the therapeutic use of these drugs prior to livestock shows and also inform livestock show authorities involved in testing for these substances.

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in alpacas.

The aim of this study was to determine the pharmacokinetics and prostaglandin E2 (PGE2 ) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight, adult, female, Huacaya alpacas. A dose of 2.2 mg/kg administered IV and 3.3 mg/kg administered TD using a cross-over design. Plasma flunixin concentrations were measured by LC-MS/MS. Prostaglandin E2 concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE2 concentrations decreased after IV flunixin meglumine administration but there was minimal change after TD application. Mean t1/2 λz after IV administration was 4.531 hr (range 3.355 to 5.571 hr) resulting from a mean Vz of 570.6 ml/kg (range, 387.3 to 1,142 ml/kg) and plasma clearance of 87.26 ml kg-1  hr-1 (range, 55.45-179.3 ml kg-1  hr-1 ). The mean Cmax, Tmax and t1/2 λz for flunixin following TD administration were 106.4 ng/ml (range, 56.98 to 168.6 ng/ml), 13.57 hr (range, 6.000-34.00 hr) and 24.06 hr (18.63 to 39.5 hr), respectively. The mean bioavailability for TD flunixin was calculated as 25.05%. The mean 80% inhibitory concentration (IC80 ) of PGE2 by flunixin meglumine was 0.23 µg/ml (range, 0.01 to 1.38 µg/ml). Poor bioavailability and poor suppression of PGE2 identified in this study indicate that TD flunixin meglumine administered at 3.3 mg/kg is not recommended for use in alpacas.

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in meat goats.

The aim of this study was to determine the pharmacokinetics and prostaglandin E2 (PGE2 ) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight adult female Boer goats. A dose of 2.2 mg/kg was administered intravenously (IV) and 3.3 mg/kg administered TD using a cross-over design. Plasma flunixin concentrations were measured by LC-MS/MS. Prostaglandin E2 concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE2 concentrations decreased after flunixin meglumine for both routes of administration. Mean λz -HL after IV administration was 6.032 hr (range 4.735-9.244 hr) resulting from a mean Vz of 584.1 ml/kg (range, 357.1-1,092 ml/kg) and plasma clearance of 67.11 ml kg-1  hr-1 (range, 45.57-82.35 ml kg-1  hr-1 ). The mean Cmax , Tmax, and λz -HL for flunixin following TD administration was 0.134 µg/ml (range, 0.050-0.188 µg/ml), 11.41 hr (range, 6.00-36.00 hr), and 43.12 hr (15.98-62.49 hr), respectively. The mean bioavailability for TD flunixin was calculated as 24.76%. The mean 80% inhibitory concentration (IC80 ) of PGE2 by flunixin meglumine was 0.28 µg/ml (range, 0.08-0.69 µg/ml) and was only achieved with IV formulation of flunixin in this study. The PK results support clinical studies to examine the efficacy of TD flunixin in goats. Determining the systemic effects of flunixin-mediated PGE2 suppression in goats is also warranted.

Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in ICR mice.

We examined the pharmacokinetic interactions of enrofloxacin and flunixin in male ICR mice that were subcutaneously (SC) administered with both or either one of the drugs. The experiments were performed on the following three groups: flunixin alone (2 mg/kg, SC), combination of flunixin (2 mg/kg, SC) and enrofloxacin (10 mg/kg, SC), and enrofloxacin alone (10 mg/kg, SC). Blood samples were collected at 5, 15 and 30 min, and 1, 2, 3, 4, 5 and 6 h after the drug administration, and the pharmacokinetic parameters of flunixin and enrofloxacin were evaluated from the plasma drug concentrations. Significant changes were detected in the pharmacokinetics of flunixin following its coadministration with enrofloxacin. Coadministration of flunixin and enrofloxacin resulted in a 41% increase of the area under the curve (AUC) and a 53% extension of the terminal half-life of flunixin; moreover, flunixin attained the maximum plasma drug concentration 2.75 times faster than when administered alone. The terminal rate constant and the maximum plasma drug concentration showed significant decreases of 34% and 33%, respectively, following the coadministration of enrofloxacin and flunixin as compared to those following the administration of flunixin alone. In contrast, no significant difference in the pharmacokinetics of enrofloxacin was detected following its coadministration with flunixin, as compared to those following the administration of enrofloxacin alone. Following the administration of enrofloxacin alone or its coadministration with flunixin, the plasma level of ciprofloxacin, the metabolite of enrofloxacin, was very low or undetectable. In conclusion, the pharmacokinetics of flunixin in ICR mice are altered by the coadministration of flunixin and enrofloxacin.

Pharmacokinetics of flunixin in the cat: enterohepatic circulation and active transport mechanism in the liver.

The plasma and urine pharmacokinetics of flunixin-meglumine (FNX) in cats were examined using a total of 12 adult animals. After an intravenous injection of FNX (2 mg/kg), the plasma concentration time curves showed a profile of a two-compartment open model with an elimination half-life of 6.6 h. In spite of high plasma protein binding (>99%), the V(d)beta was unusually large, 0.7 L/kg. Although the recovery of FNX from urine was only 0.4% of the dose, the estimated inherent renal clearance closely corresponded to the renal plasma flow rate, indicating that a renal active tubular secretion was involved in the pharmacokinetics of FNX. Cholestyramine (ChSA), an anion exchanger, was orally administered immediately before the FNX injection in order to determine the involvement of enterohepatic circulation in FNX pharmacokinetics. The elimination phase of the profile of FNX was prevented by the concomitant administration of ChSA, so it was concluded that the drug undergoes enterohepatic circulation in cats. Pravastatin (PV) is a specific substrate of the type-2 organic anion transporting polypeptide transporter (OATP-2) in human liver cells. The effect of a concomitant intravenous injection of PV with FNX was examined in order to determine the involvement of OATP-2 like transporter in the pharmacokinetics. The V1 and total body clearance were decreased after the injection of PV. In conclusion, at least two active transport mechanisms are involved in the pharmacokinetics of FNX in cats. One pathway is renal tubular secretion and the other is sinusoidal active uptake by liver cells. The latter may be responsible for the enterohepatic circulation of FNX in cats.

Estudio comparativo de la actividad analgésica de clonixinato de lisina y naproxeno sódico en el control del dolor postoperatorio en cirugía oral / Comparative study of analgesic activity of lisine clonixinate and sodic naproxene in postsurgical pain control after oral surgery

El objetivo de la presente investigación fue comparar la actividad analgésica de clonixinato de lisina con el naproxeno sódico en el dolor postoperatorio subsecuente a la cirugía oral. Utilizando el método doble-ciego, dosis únicas de clonixinato de lisina 125 mg. o de naproxeno sódico 550 mg. se administraron por selección al azar a 92 pacientes con dolor postoperatorio después de efectuar extracciones de terceros molares incluidos. Durante un periodo de control de 4 horas posterior a la ingestión oral de cada una de las medicaciones estudiadas, se evaluaron en cada paciente

Determination of pharmacokinetics and pharmacodynamics of flunixin in calves by use of pharmacokinetic/pharmacodynamic modeling.

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 mg/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surgically implanting tissue cages at subcutaneous sites and stimulating the tissue cage granulation tissue by intracavitary injection of carrageenan. The actions of flunixin on exudate concentrations of several substances related to the inflammatory process, including proteases (metalloprotease [active and total] and cysteine and serine proteases), enzymes (lactate dehydrogenase, acid phosphatase, and beta-glucuronidase [beta-glu]), eicosanoid (prostaglandin E2 [PGE2], leukotriene B4, and serum thromboxane B2 [TXB2]) concentrations, and bradykinin (BK)-induced edema, were investigated. Flunixin had a long elimination half-life--6.87 +/- 0.49 hours--and volume of distribution was 2.11 +/- 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 +/- 0.03 L/kg/h. Flunixin exerted inhibitory effects on serum TXB2 and exudate PGE2 concentrations, beta-glu activity, and BK-induced swelling. Other enzymes and inflammatory mediators were not significantly affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Gas chromatographic analysis of flunixin in equine urine after extractive methylation.

A quantitative method for the analysis of flunixin, 2-(2-methyl-3-trifluoromethylanilino) nicotinic acid, in equine urine by gas chromatography with nitrogen-phosphorus detection has been developed. Flunixin and the internal standard, mefenamic acid, N-(2,3-xylyl) anthranilic acid, were analysed after extractive methylation of the carboxylic acid group using methyl iodide. The extraction and alkylation conditions of flunixin and mefenamic acid have been studied. The detection limit of the method was 0.25 mumol/l flunixin in urine (74 ng/ml). Flunixin was found to be conjugated to 96.5% in equine urine, and the conjugate was spontaneously hydrolysed to free flunixin. This approach can also be used to confirm the presence of flunixin or mefenamic acid in horse urine in the doping control of racehorses.