Pharmacokinetics And Bioequivalence Of Meloxicam Chewable Tablets In Dogs

Meloxicam is a new non-steroidal anti-inflammatory drug.It is a COX-2 selective inhibitor,and it has strong analgesic and anti-inflammatory effects.Because of its few adverse reactions,many countries have used it to replace other non-steroidal anti-inflammatory drugs,it is widely used in analgesia,anti-arthritis(OAA),rheumatoid arthritis(RA)and other acute or chronic inflammation.Meloxicam is also one of numbers of currently approved non-steroidal anti-inflammatory drugs(NSAIDs)for clinical application in dogs.European approved meloxicam tablets and oral suspensions could be used to relieve inflammation and pain caused by acute or chronic musculoskeletal diseases in dogs.In this study,we established a high performance liquid chromatography method to determine the concentration of meloxicam in plasma of dogs.According to the relevant specifications of the bioequivalence test,the domestic meloxicam tablets was used as a reference.Bioequivalent tests were performed to determine whether the domestic meloxicam chewable tablets could substitute the original drug in clinic.1.A method for the determination of meloxicam in Canine Plasma by High performance liquid ChromatographyMeloxicam was extracted by liquid-liquid extraction,separating drug in plasma of dogs with Agilent HC-C18(250×4.6 mm,5 ?m)column,useing isocratic elution,each component of the sample was quantified using the Agilent 1260 chromatographic system.Analysis based on the external standard method.The mobile phase consisted of acetonitrile-0.1%phosphoric acid aqueous solution(pH 2.5)=65:35(V/V)and delivered at a flow rate of 1 mL/min,the column temperature:35?,the injection volume was 20 ?L,UV detection wavelength was set at 355 nm.This analysis yielded a standard curve that was linear between 0.05 and 5?g/mL meloxicam with a correlation coefficient of 0.999.The limit of detection(LOD)and limit of quantification(LOQ)of the method were 0.02 ?g/mL and 0.05 ?g/mL,respectively.The inter-assay recoveries of meloxicam(0.05,1,5 ?g/mL)were within 82%?108%,and the coefficient of variation was less than 8%.The results of stability test show that the samples of stock solution and test had good stability under the condition of refrigeration.room temperature and repeated freeze-thaw cycles.The assay for the determination of meloxicam in plasma from dogs established in this study can be used to accurately detect meloxicam in the plasma of dogs.2.Pharmacokinetic and bioequivalence of meloxicam chewable tablets in dogsEighteen adult Beagles with the similar body weight were randomly divided into two groups,using cross experiment design.The first stage,1-9 dog single dose(0.25mg/kg bw)was administered orally with the test meloxicam chewable tablets,and the 10-18 dogs single dose(0.25mg/kg bw)was taken orally with the reference meloxicam chewable tablets;In the second stage,1-9 dog single dose(0.25mg/kg bw)was taken orally with the reference meloxicam chewable tablets,and the 10-18 dogs single dose(0.25mg/kg bw)was taken orally with the test meloxicam chewable tablets.The two-phase wash period was two weeks.Blood samples were collected at predetermined time points after' administration.The meloxicam content in plasma samples was determined using a validated HPLC method.A curve was fitted to the plasma concentration versus time data by using the Winnonlin 6.4 software program.According to the guiding principle of the bioequivalence test of veterinary chemicals,it was determined whether the test product and the reference product were bioequivalent.After oral administration of a single oral dose of meloxicam chewable tablets to the test and reference product,the average elimination half-life(ti/2)were(19.0±5.4)h and(21.3±3.4)h,respectively.The peak time(Tmax)were(4.1±2.1)h and(4.9±1.6)h,and the peak concentration(Cmax)were(0.896±0.159)?g/mL and(0.816±0.203)?g/mL,respectively.The mean retention time(MRT)were(20.6±3.1)h and(22.5±2.7)h,respectively.The area under the average drug-time curve(AUC0-t)were(22.121 ±3.512)?g·h·mL-1 and(19.807±3.963)?g·h·mL-1),respectively.the relative availability(F)of meloxicam was 111.81%.The results of pharmacokinetic fitting showed that the oral administration of meloxicam chewable tablets was eliminated slowly in dogs,and the test products and reference products had similar pharmacokinetic characteristics in dogs.There was no significant difference in the pharmacokinetic parameters between the test product group and the reference product group of meloxicam chewable tablets(p>0.05),The bioequivalence of Cmax(logarithmic conversion),AUC0-t(logarithmic conversion)and AUC-?.(logarithmic conversion)was tested by the WINNONLIN 6.4 version of the parameter calculation software.The ratio of the logarithmic mean value of the test product to the reference product Cmax was 109.93%,the 90%confidence interval was 96.63%to 125.06%,the 90%confidence interval of meloxicam Cmax was somewhere between 70%and 143%;The ratio of the logarithmic mean value of the test product to the reference product AUC0-t was 111.81%,the 90%confidence interval was 103.56%to 120.72%;The ratio of the logarithmic mean value of the test product to the reference product AUC0-? was 112.68%,the 90%confidence interval was 104.38%to 121.63%.The 90%confidence interval of meloxicam AUC was somewhere between 80%and 125%.The results showed that the test samples and reference products were bioequivalent and can be clinically substituted for each other.