The pharmacokinetics of transdermal flunixin meglumine in Holstein calves

This study describes the pharmacokinetics of topical and intravenous (IV) flunixin meglumine in Holstein calves. Eight male Holsteins calves, aged 6 to 8 weeks, were administered flunixin at a dose of 2.2 mg/kg intravenously. Following a 10‐day washout period, calves were dosed with flunixin at 3.33 mg/kg topically (transdermal). Blood samples were collected at predetermined times from 0 to 48 h for the intravenous portions and 0 to 72 h following topical dosing. Plasma drug concentrations were determined using liquid chromatography with mass spectroscopy. Pharmacokinetic analysis was completed using noncompartmental methods. The mean bioavailability of topical flunixin was calculated to be 48%. The mean AUC for flunixin was determined to be 13.9 h × ug/mL for IV administration and 10.1 h × ug/mL for topical administration. The mean half‐life for topical flunixin was 6.42 h and 4.99 h for the intravenous route. The C_max following topical application of flunixin was 1.17 μg/mL. The time to maximum concentration was 2.14 h. Mean residence time (MRT) following IV injection was 4.38 h and 8.36 h after topical administration. In conclusion, flunixin when administered as a topical preparation is rapidly absorbed and has longer half‐life compared to IV administration.     

Intravenous pharmacokinetics of moxifloxacin following simultaneous administration with flunixin meglumine or diclofenac in sheep

In this study, the pharmacokinetics of moxifloxacin (5 mg/kg) was determined following a single intravenous administration of moxifloxacin alone and co-administration with diclofenac (2.5 mg/kg) or flunixin meglumine (2.2 mg/kg) in sheep. Six healthy Akkaraman sheep (2 ± 0.3 years and 53.5 ± 5 kg of body weight) were used. A longitudinal design with a 15-day washout period was used in three periods. In the first period, moxifloxacin was administered by an intravenous (IV) injection. In the second and third periods, moxifloxacin was co-administered with IV administration of diclofenac and flunixin meglumine, respectively. The plasma concentration of moxifloxacin was assayed by high-performance liquid chromatography. The pharmacokinetic parameters were calculated using a two-compartment open pharmacokinetic model. Following IV administration of moxifloxacin alone, the mean elimination half-life (t_1/2β), total body clearance (Cl_T), volume of distribution at steady state (V_dss) and area under the curve (AUC) of moxifloxacin were 2.27 hr, 0.56 L h⁻¹ kg⁻¹, 1.66 L/kg and 8.91 hr*µg/ml, respectively. While diclofenac and flunixin meglumine significantly increased the t_1/2β and AUC of moxifloxacin, they significantly reduced the Cl_T and V_dss. These results suggest that anti-inflammatory drugs could increase the therapeutic efficacy of moxifloxacin by altering its pharmacokinetics.     

Effect of age and training status on pharmacokinetics of flunixin meglumine in thoroughbreds

The effect of age and training status on the pharmacokinetics of flunixin meglumine was evaluated in 16 Thoroughbreds. Horses were assigned to 1 of 3 groups on the basis of age and training status: group A (n = 6), horses in active training and less than or equal to 5 years old; group B (n = 5), horses out of training for a minimum of 6 weeks and less than or equal to 5 years old; and group C (n = 5), horses out of training for at least 2 years and greater than or equal to 9 years old. After administration of 500 mg of flunixin meglumine IV, multiple serum and urine samples were obtained over 24 hours and assayed for flunixin by high-performance liquid chromatography. Although the mean distribution rate constant and volume of distribution were similar for the 3 groups, mean total body clearance and elimination rate constant were significantly (P less than 0.05) greater and half-life significantly (P less than 0.01) less in groups A and B, compared with group C. Differences in pharmacokinetic values were not observed between the horses in group A and B. In addition, the changes in clearance, elimination rate constant, and half-life of flunixin were found to significantly (P less than 0.05) correlate with age. The results of this investigation indicated that age, but not training status, influences disposition of flunixin meglumine in Thoroughbreds.     

Pharmacokinetics of flunixin meglumine in the cow

Plasma levels of flunixin were measured in heifers after a single intravenous injection (1.1 mg kg-1), using high performance liquid chromatography. Plasma concentration versus time curves were best described by a two compartment model. The distribution phase (alpha) half-life was 0.294 hours, the elimination phase (beta) half-life was 8.12 hours and the volume of distribution was 1050 ml kg-1.     

Pharmacokinetics of flunixin meglumine in dogs

The pharmacokinetics of flunixin meglumine, a potent nonsteroidal anti-inflammatory agent, were studied in 6 intact, awake dogs. Plasma samples were obtained up to 12 hours after IV administration of flunixin meglumine. Flunixin concentration was determined, using high performance liquid chromatography. Plasma data best fit a 2-compartment model. Distribution half-life was 0.55 hour; elimination half-life was 3.7 hours; volume of distribution (area) was 0.35 L/kg; volume of distribution at steady state was 0.18 L/kg; volume of the central compartment was 0.079 L/kg; and total body clearance was 0.064 L/hr/kg. Flunixin concentrations obtained over a 6-hour period in 3 dogs with septic peritonitis did not differ significantly from those obtained from healthy dogs.     

Chronic flunixin meglumine therapy in foals

Effects of a therapeutic dose of flunixin meglumine on gastric mucosa of horse foals were determined by endoscopy, double-contrast radiography, and gross and histologic examinations. Foals were administered 1.1 mg of flunixin meglumine/kg of body weight, PO/day for 30 days in an encapsulated form that was divided into 2 doses/day (group 1; n = 3) or by IM injection once a day (group 2; n = 7). Three control foals (group 3; n = 3) were administered capsules (n = 1) containing dextrose powder or IM injections (n = 2) of vehicle solution without flunixin meglumine. All 3 groups-1 foals given flunixin meglumine PO developed oral ulcers. Group-2 foals given flunixin meglumine IM did not develop oral ulcers. One control foal (group 3) developed 1 oral ulcer that healed during the study. Endoscopic examination revealed linear crease-like mucosal lesions in the glandular portion of the stomach in 2 group-2 foals. Radiographic evidence of gastric ulcers was observed in only 1 gastrogram of a group-1 foal. Foals were euthanatized, and necropsy revealed erosions and/or ulcers of the glandular portion of the stomach. Oral ulcers were observed in all 3 group-1 foals. Erosions of the glandular portion of the stomach developed in all 10 foals given flunixin meglumine, but did not develop in group-3 foals. Ulceration of the glandular portion of the stomach was present in 1 group-2 foal.     

Effect of body weight on the pharmacokinetics of flunixin meglumine in miniature horses and quarter horses

In most species, large variations in body size necessitate dose adjustments based on an allometric function of body weight. Despite the substantial disparity in body size between miniature horses and light‐breed horses, there are no studies investigating appropriate dosing of any veterinary drug in miniature horses. The purpose of this study was to determine whether miniature horses should receive a different dosage of flunixin meglumine than that used typically in light‐breed horses. A standard dose of flunixin meglumine was administered intravenously to eight horses of each breed, and three‐compartmental analysis was used to compare pharmacokinetic parameters between breed groups. The total body clearance of flunixin was 0.97 ± 0.30 mL/min/kg in miniature horses and 1.04 ± 0.27 mL/min/kg in quarter horses. There were no significant differences between miniature horses and quarter horses in total body clearance, the terminal elimination rate, area under the plasma concentration versus time curve, apparent volume of distribution at steady‐state or the volume of the central compartment for flunixin (P > 0.05). Therefore, flunixin meglumine may be administered to miniature horses at the same dosage as is used in light‐breed horses.     

Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma,exudate and transudate in sheep

Flunixin meglumine (FM, 1.1 mg/kg) and phenylbutazone (PBZ, 4.4 mg/kg) were administered intravenously (i.v.) as a single dose to eight sheep prepared with subcutaneous (s.c.) tissue-cages in which an acute inflammatory reaction was stimulated with carrageenan. Pharmacokinetics of FM, PBZ and its active metabolite oxyphenbutazone (OPBZ) in plasma, exudate and transudate were investigated. Plasma kinetics showed that FM had an elimination half-life (t_½β) of 2.48 ± 0.12 h and an area under the concentration – time curve (AUC) of 30.61 ± 3.41 μg/mL.h. Elimination of PBZ from plasma was slow (t_½β = 17.92 ± 1.74 h, AUC = 968.04 ± μg/mL.h.). Both FM and PBZ distributed well into exudate and transudate although penetration was slow, indicated by maximal drug concentration (C_max) for FM of 1.82 ± 0.22 μg/mL at 5.50 ± 0.73 h (exudate) and 1.58 ± 0.30 μg/mL at 8.00 h (transudate), and C_max for PBZ of 22.32 ± 1.29 μg/mL at 9.50 ± 0.73 h (exudate) and 22.07 ± 1.57 μg/mL at 11.50 ± 1.92 h (transudate), and a high mean tissue-cage fluids:plasma AUC_last ratio obtained in the FM and PBZ groups (80–98%). These values are higher than previous reports in horses and calves using the same or higher dose rates. Elimination of FM and PBZ from exudate and transudate was slower than from plasma. Consequently the drug concentrations in plasma were initially higher and subsequently lower than in exudate and transudate.     

The impact of pain on the pharmacokinetics of transdermal flunixin meglumine administered at the time of cautery dehorning in Holstein calves

Objective

To study the influence of pain on the pharmacokinetics and anti-inflammatory actions of transdermal flunixin administered at dehorning.

Disposition and excretion of flunixin meglumine in horses

The disposition of flunixin meglumine administered IV at a dosage of 1.1 mg/kg was described by a 2-compartment model; the alpha and beta half-lives (t1/2) were 0.61 and 1.5 hours, respectively. When administered IV at a rate of 2.2 mg/kg, the disposition was best described by a 3-compartment model, and the alpha, beta, and lambda t1/2 were 0.16, 1.52, and 6.00 hours, respectively. The zero-time plasma concentrations after flunixin meglumine was administered at 1.1 and 2.2 mg/kg were 9.3 +/- 0.76 and 21.5 +/- 7.4 mg/L, respectively. The bioavailability after oral administration of 1.1 mg/kg was 85.8%. The absorption t1/2 was 0.57 hours, with a peak concentration of 2.50 +/- 1.25 mg/L. The cumulative urinary recoveries for IV and oral administrations were 61.0% and 63.3%, respectively, of the dose for the 12-hour collection period. The final asymptotic points of urine excretion after IV and oral administrations were 406.4 +/- 65.5 and 357.7 +/- 53.5 mg, respectively, which represented 75.5 and 77.5% of the drug accounted for between 30 and 35 hours after administration. Flunixin meglumine was rapidly excreted in urine over a 2- to 4-hour period after drug administration and was highly bound to protein in plasma.     

氟尼辛葡甲胺对血液内毒素的影响

为研究氟尼辛葡甲胺对血液内毒素的影响,本实验选择预产期相近的长大母猪20头,随机分为实验组和对照组各10头。实验组母猪于分娩前15 d直至断奶,每1 000 kg日粮中添加1 kg高热血毒清(含10%氟尼辛葡甲胺),对照组不添加高热血毒清。采用鲎试验法检测内毒素、使用全自动生化分析仪测定肝功能、通过临床症状评估发病率。结果显示:实验组母猪和仔猪血液内毒素含量均极显著低于对照组(p0.01);实验组母猪便秘发生率、子宫内膜炎发生率、仔猪腹泻发生率和仔猪死亡率极显著低于对照组(p0.01);实验组母猪分娩前3 d至分娩后2 d的体温显著低于对照组(p0.05);实验组各日龄仔猪血清丙氨酸氨基转移酶和天门冬氨酸氨基转移酶均显著低于对照组(p0.05),γ-谷氨酰转移酶极显著低于对照组(p0.01)。本研究结果表明氟尼辛葡甲胺具有较强的抗内毒素作用,可以改善仔猪肝功能,为控制内毒素对猪的不良作用提供实验依据。     

新兽药氟尼辛葡甲胺的解热镇痛作用

通过小鼠醋酸扭体法、家兔蛋白胨致热法对氟尼辛葡甲胺的解热、镇痛作用进行了研究。结果表明,氟尼辛葡甲胺具有明显的解热、镇痛作用。和对照组相比,氟尼辛葡甲胺4个剂量组（1.25、2.5、5、10 mg/kg）对醋酸所致的小鼠扭体反应均有极强的抑制作用,抑制率最高达100%。2.5 mg/kg的氟尼辛葡甲胺镇痛率即达82.7%,明显强于双氯芬酸钠（65.4%）和安乃近（58.7%）。对蛋白胨所致家兔发热的解热效果,氟尼辛葡甲胺高剂量组（4 mg/kg）优于安乃近组（0.2 g/kg）（P〈0.05）和氨基比林组（0.2 g/kg）（P〈0.01）。中剂量氟尼辛葡甲胺组（2 mg/kg）作用稍逊于安乃近组,但差异不显著。低剂量氟尼辛葡甲胺组（1 mg/kg）作用与氨基比林组相当。     

Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs

OBJECTIVE: To examine pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs following simultaneously administered SC injections of these drugs. ANIMALS: 10 Beagles (4 males and 6 females). PROCEDURE: All dogs underwent the following 3 drug administration protocols with a 4-week washout period between treatments: flunixin administration alone (1 mg/kg, SC); simultaneous administration of flunixin (1 mg/kg, SC) and enrofloxacin (5 mg/kg, SC); and enrofloxacin administration alone (5 mg/kg, SC). Blood samples were collected from the cephalic vein at 0.5, 0.75, 1, 1.5, 2, 3, 5, 8, 12, and 24 hours following SC injections, and pharmacokinetic parameters of flunixin and enrofloxacin were calculated from plasma drug concentrations. RESULTS: Significant increases in the area under the curve (32%) and in the elimination half-life (29%) and a significant decrease (23%) in the elimination rate constant from the central compartment of flunixin were found following coadministration with enrofloxacin, compared with administration of flunixin alone. A significant increase (50%) in the elimination half-life and a significant decrease (21%) in the maximum plasma drug concentration of enrofloxacin were found following coadministration with flunixin, compared with administration of enrofloxacin alone. CONCLUSIONS AND CLINICAL RELEVANCE: The observed decrease in drug clearances as a result of coadministration of flunixin and enrofloxacin indicates that these drugs interact during the elimination phase. Consequently, care should be taken during the concomitant use of flunixin and enrofloxacin in dogs to avoid adverse drug reactions.     

The efficacy of dexamethasone and flunixin meglumine in treating endotoxin-induced changes in calves

Eicosanoids have been implicated in the pathophysiology of endotoxic shock. Drugs which alter eicosanoid production such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAID) are beneficial in treating endotoxic shock. Experiments were conducted to investigate the efficacy of dexamethasone, a corticosteroid, and/or flunixin meglumine, a NSAID, in treating endotoxin-induced changes in calves.Fourteen male calves were assigned to one of four treatment groups: group 1, endotoxin-untreated; group 2, endotoxin-flunixin meglumine treated; group 3, endotoxin-dexamethasone-treated; group 4, endotoxin-flunixin meglumine and dexamethasone-treated. Each calf was given three intravenous and intraperitoneal injections of E. coli endotoxin. Hemodynamic, blood gas, blood chemical and eicosanoid level determinations were obtained.Thirty minutes after endotoxin injection, pulmonary artery pressure (PAP) increased and cardiac output (CO) decreased compared with baseline, corresponding to increased thromboxaneB₂ levels in groups 1 and 3. These groups exhibited a decreased mean arterial pressure (MAP) at three and five hours corresponding to increased 6-keto-prostaglandinF_lalpha. The MAP, PAP and CO of group 4 remained near baseline for the entire six hours, except for a late drop in MAP. Lactic acid levels were significantly increased and arterial bicarbonate levels were reduced by six hours in all groups except for group 4. These results indicate that the combination treatment of flunixin meglumine and dexamethasone prevents many of the metabolic derangements observed during endotoxic shock in calves.     

Effects of flunixin meglumine in dogs following experimentally induced endotoxemia

Twelve dogs were randomly divided into three groups. Group 1 dogs were given Escherichia coli endotoxin and then treated with flunixin meglumine. Group 2 dogs were given endotoxin as group 1, but untreated. Group 3 dogs were given flunixin meglumine alone. The dogs were monitored clinically and urine and serum samples were collected at regular intervals for 72 hours. All surviving dogs were humanely killed after 72 hours and examined for gross and histologic lesions. Group 1 dogs all survived 72 hours, but showed prerenal azotemia, hepatocellular damage, hemorrhagic enteritis, and numerous gastric ulcerations. Three of the four dogs in group 2 died before 72 hours. Group 2 dogs showed many of the same chemical and hemodynamic changes as group 1. They had severe hemorrhage into the intestinal lumen; however, there were no gastric ulcerations. Group 3 dogs all survived and showed little physical or hematologic change. The study suggested the following: 1) flunixin meglumine was an effective drug in ameliorating the fatal effects of canine endotoxemia, 2) the effects of endotoxin in combination with flunixin meglumine, at 1.1 mg/kg body weight, caused gastric ulcerations, and 3) in normal dogs flunixin meglumine at 1.1 mg/kg body weight did not cause severe side effects or gross lesions.