Pharmacokinetic parameters of meloxicam after its oral administration in goat

Aim: The objective of the present study was to find out the levels of analgesic drug meloxicam in the blood plasma of young goats. The drug was given to them through oral route. Data was used to elucidate the Pharmacokinetic determinants of the drug which were employed to arrive at the dose schedule and frequency of the drug in goats. Materials and Methods: Elaborate pharmacokinetic research of the drug meloxicam was done on 18 to 24 months old, five adult male local goats (Capra hircus) of Assam weighing 20 to 25 kg.The drug was given orally at the dose rate of 0.35 mg/kg at the Goat Rearing farm, Guwahati, Assam. Analysis of blood was done by high performance liquid chromatography (HPLC) system. Results: The mean values of area under curve (AUC) and mean area under curve (AUMC) were 3137.488 ± 125.3749 2 μg.min/ml and 4650460 ± 380892.4744 μg.min /ml respectively .The mean peak plasma level of meloxicam was 1.972 ± 0.0477 μg/ml at 600 min. The mean values of elimination half life (t ) and absorption half life (t ) were 693±0.00 min and 1/2β 1/2Ka 170.6 ± 17.0076 min respectively. The mean values of volume of distribution (Vd) and mean residence time (MRT) were 0.114 ± 0.0156 L/kg and 1472.264 ± 63.336 min respectively. The mean value of T was found to be 497 ± 19.8040 min. Following max single oral administration the minimum effective therapeutic concentration or minimum effective plasma concentration of meloxicam was detectable up to 1200 min. The bioavailibity (F) of the drug was 80.5 ± 10.0150%. Conclusion: These pharmacokinetic determinants were used to determine the frequency and dose schedule of meloxicam in goats. The minimum effective concentration of the drug is 0.7 μg/ml in plasma. To maintain this, an initial loading dose of 0.5 mg/kg body weight should be followed by a maintenance dose of 0.4 mg/kg body weight/10 hour.


Introduction
inflammation, muscular pain, joint pain, rheumatic pain, neuralgia, soft tissue injuries and immobility Meloxicam is a potent anti-inflammatory agent, associated with lameness, arthritis and myositis [1,4, being a relatively selective Cox-2 inhibitor [1], in 5].In veterinary practice Meloxicam was introduced comparison to older non-steroidal anti inflammatory for management of canine osteoarthritis and since then drugs (NSAIDs) which none selectively also inhibit it is being used for the management of pain and infla-Cox-1 isoenzyme, leading to serious gastrointestinal mmation, arising from both acute and chronic conditions and renal side effects.Meloxicam is 12 times more [3,7,8].In cattle it is used to treat pain, mastitis, selective in inhibiting Cox-2 activity than Cox-1 activity pneumonia and other inflammatory conditions [9,10].[2,3].The higher selectivity results in low ulcerogenic Indications for meloxicam use in farm animals include potential and less gastrointestinal irritation as compared respiratory infections and acute mastitis [11].It is being to other NSAIDs [4,5].This less toxicity of the drug increasingly used in manage-ment of musculoskeletal makes it a broad spectrum drug covering a varying disorders for reduction in pain and inflammation [12].number of diseases.In conjunction with a suitable Pharmacokinetic profile of meloxicam has been antibiotic, it is used as a drug of choice in many diseases elucidated in human beings [1,4], cattle [10,11], sheep [4,5].Meloxicam prevents ongoing occurrence of and goat [13,14], rabbit [15], vulture [16], horses [17], inflammation by inhibiting prostaglandin production, camels [18], piglets [19], green iguanas [20], cats [21], that sensitize the afferent nociceptors at peripheral sites llamas [22] and many other species of animals..But of inflammation [6,7].
data of one species cannot be extrapolated and used in In man it is used for treating non descriptive other species due to high interspecies variation in the pyrexia, painful conditions due to acute and chronic metabolism of meloxicam.Interspecies variation along with local and regional factors further compound the problem.Goat is called as poor man's cow owing to its utility and popularity among the farmers of India.Also much information is not available on the pharmaco-5ml syringe from all the goats, into vacuntainer heparikinetic profile of this drug in small ruminants.Hence nized tubes before and after the drug administration.the present study was conducted to determine the Blood was collected at 30, 45, 60, 120, 180, 240, 360, complete pharmacokinetics, dosing schedule and dosing 480, 540, 600, 720, 840, 1440 and 2880 minutes frequency of this drug after its oral administration in respectively.Blood samples were centrifuged at 3600 the domestic goat of Assam.
rpm for 12 minutes and the plasma thus extracted was stored in 1.5ml capped micro-centrifuge tubes in a

Materials and Methods
refrigerator at -5ºC till further processing which was Experimental animals: Experimental animals were 20 done within 5 days of plasma collection.The drug was to 24 months old, five male goats (Capra hircus) of quantitatively estimated from the plasma of animals by Assam, with body weight ranging between 20 to 25 kg.
advanced Baert and De Backers HPLC method [23].Clinically all the animals were sound and healthy and Mobile phase used for chromatography was a mixture were raised at Goat rearing farm, Guwahati, Assam.
of 65% water: acetic acid (99:1, v/v) and 35 % acetonitrile with a flow rate of 0.8 ml/min.Drug detection Ethical approval: Adherence to all the concerned ethical was done at 355 nm wavelength.Column temperature principles as enumerated by the International Animal of the oven was 35 ºc and drugs retention time was 6.65 Ethics Committee, was observed strictly throughout min.the course of this study.Animals were handled gently and carefully.Deworming was done one month before Chemical assay of meloxicam: The above collected the start of experimentation with the help of fenbenplasma was used for the analysis of the drug.0.5 ml of dazole which was given at the rate 1ml/kg body weight.
plasma was mixed with 0.5 ml of acetonitrile.Vortex Mixer was used to mix the two and the mixture was Instruments used: High performance liquid chromathen centrifuged for 20 minutes at 6200 rpm.Clear tography (HPLC) system.Waters HPLC system supernatant was collected and 0.5 ml of HPLC grade consisting of a Degasser, two pumps A and B (Waters water was added to it.The aliquot thus obtained was 515 HPLC pump), an injector, C-18 symmetry column filtered through 0.22 µm nylon filter paper.20 µl of this (particle size 5 µm; 4.6 mm x 250 mm), Waters 2487 filtrate was introduced into HPLC system.dual λ absorbance detector and a screen was used.(Waters Breeze Software, Ireland).Centrifuge machine Preparation of standard curve: Drug free plasma was (Labnet).Two micropipettes 100 µl (fixed) and 2-20 µl spiked with the standard meloxicam at a concentration (adjustable).Vortex mixer cum shaker.BD Vacuntainer of 0.5, 1.0, 1.75, 2.5, 5.0, 7.5, 10.0, 15.0 and 20.0 µg/ ml (sodium Heparin [NH] 68 USP units plus blood of plasma and then plasma standards were prepared.collection tubes, 5ml).Tarpons 1.5 ml micro-centrifuge Quantification of drug was done from its respective tubes.0.22 µm nylon filter.Test tubes, Flasks, measuring peak area and calibration curves were employed to cylinders, spirit, cotton, scissors.Syringes (2 ml and 5 determine the concentration of drug in plasma samples.ml).
Determination of meloxicam concentration in a repre-Drugs and chemicals used: Pure standard Meloxicam sentative sample of goat is depicted in Figure -1.(Meloxicam oral suspension BP vet, 1.5 mg/ml, Melo-Pharmacokinetic analysis of data: Log of plasma drug xicam i.v solution 5 mg/ml).HPLC grade Acetonitrile concentration versus time profile was employed to and HPLC grade water.
arrive at pharmacological determinants of every animal Estimation of meloxicam: A single dose of meloxicam by Gibaldis "two compartment open model" [24].was administered orally into the animals at the rate of Mean and SE for each determinant was obtained from 0.35 mg/kg as per their body weights.Blood samples (5 the whole data.Standard statistical method was employed ml) were collected from jugular vein with the help of a for statistical interpretation [25].

presented in Table-1.
Mean peak plasma level of drug was 1.972± 0.047 Amount of the drug present in the plasma samples µg/ml at 600 min, which decreased quickly to 1.314± of the goats at different time periods was used to 0.0271 µg/ml at 840 min of time.From this time onwards elucidate different pharmacokinetic determinants.
the decrease is uniform and the smallest concentration Magnitude of drug at varying times in the plasma of of about 0.3314±0.0271µg/mlwas detected at 2880 goats after its single oral administration has been   380892.4744µg/min /ml respectively.The mean value bioavailibity (F) were found to be 497 ± 19.8041 min of volume of distribution (Vd) was 0.114 ± 0.156 L/kg and 80.5 ± 10.01498 % respectively.0.7 µg/ml of which is less than cattle (0.242 L/kg) [10].This plasma is the minimum effective therapeutic concenindicates that the meloxicam is well distributed in tration of drug and it was present up to 1200 min after a cattle than in goats when given orally.single oral administration.The mean values of AUC and AUMC were 3137.488±125.3749µg/min/ml and  [15] body weight/10 hours is advised to maintain its and Vultures [16].The mean peak plasma level of effective concentration.The elimination of the drug meloxicam was 1.972 ± 0.0476 at 600 min, which was slow and the mean value of volume of distribution declined rapidly to 1.314 ± 0.0271 µg/ml at 840 min of (Vd) was lesser after oral administration which time, thereafter the decline was steady and the lowest indicates that the overall absorption and distribution of concentration of 0.334 ± 0.0282 µg/ml was observed at the drug after oral administration was very slow when 2880 min.compared to intravenous route of administration.Mean The time to achieve maximum plasma residence time is more than double after oral concentration (T ) was found to be 497 ± 19.8040 max administration than after IV administration min which was less than that observed in calves [9,10] Authors' contributions but was more than dogs (450 min) [26,27] and rabbits (360 min) [15].This implies that the peak drug Implementation of study design, experimentation and concentration is achieved rapidly in the plasma of goats data recording was done by ARW and RKR.SUN, in comparison to cattle.
OSS, SAB and NAK carried out analysis.ARW drafted The value of bioavailibity (F) was found to be and revised the manuscript.All the authors read and 80.5 ± 10.0150 % in the present study.This is less than approved the final manuscript.that found in cattle (100%) and horses (98 %) [10,17].

Figure- 1 .
Figure-1.Plasma concentration of Meloxicam in HPLC data system after oral administration

Figure- 2 .
Figure-2.Mean plasma values of Meloxicam in goat after oral administration at the dose rate of 0.35 mg/kg.

Table - 1
. Plasma concentrations (µg/ml) of meloxicam in goat after oral administration at the dose rate of 0.35mg/kg body weight.

Table -
2. Pharmacokinetics of Meloxicam after single oral administration at the dose rate of 0.35 mg/kg in goat.(n=5)

Time(minutes) Units Animals (n=5) Mean ± SE
[4]s decrease of drug with respect time in goat present study was 1472.264 ± 63.3305 min which is plasma has been depicted in Figure-2.significantlylowerthan in cattle (2700 min)[9,10], This quantification of meloxicam in plasma samples again indicating that the drug is excreted quickly in of goat was used to arrive at different pharmacokinetic goats than in cattle.This is supported by the fact that determinants which have been presented in Table-2.meloxicam has a bit more tissue binding in cattle than The value of elimination half-life (t ) was 693 ± in goat[4].The values of AUC and AUMC obtained Effective concentration of the drug was present upto 20 hours inIn the present study, meloxicam was administered the blood plasma.Following oral administration of orally at a dose rate of 0.35 mg/kg of body weight in meloxicam, an initial loading dose of 0.5 mg/kg body goats.Similar dose rate in the range of 0.2 to 0.6 mg/kg weight succeeded by a maintenance dose of 0.4 mg/kg of body weight were used in horses [17], rabbits Discussionof its better dissolution and absorption.