The Pharmacokinetic Study Of A Xanthine Oxidase Inhibitor Compound WSJ-537

Objective:WSJ-537 is a kind of xanthine oxidase inhibitor synthesized by using febuxostat as template.In the previous in vitro pharmacological experiment,the inhibitory activity of xanthine oxidase was better than that of febuxostat.In this paper,a method to determine the concentration of WSJ-537 in rat plasma,tissue and excretion samples was established,and the pharmacokinetics,tissue distribution and excretion process of WSJ-537 in rats were studied.Methods:1.To determine the concentration of WSJ-537 in SD rat plasma,an LC-MS/MS method was established.The pharmacokinetics of WSJ-537 in rats was investigated after oral administration of low(1.7 mg·kg^-1),medium(5.2 mg·kg^-1)and high(15.5 mg·kg^-1)and intravenous injection of 5.2 mg·kg^-1.2.To determine the concentration of WSJ-537 in SD rats tissues,an LC-MS/MS method was established,and the tissue distribution behavior of WSJ-537 in SD rats was investigated after a single dose oral administration of 5.2 mg·kg^-1.3.An LC-MS/MS method was established for the determination of WSJ-537 in SD rats urine and feces.After a single dose oral administration of 5.2 mg·kg^-1,the cumulative excretion of WSJ-537 in urine and feces of rats was determined,and the excretion behavior of WSJ-537 in rats in the form of prototype drug was investigated.Results:1.The time to peak concentration(T_max)of oral administration of three oral administration groups were all less than 1.5 h,and the half-life(T_1/2)were less than 3.5 h.The linear regression equation between AUC_0-??y?and dose?x?of the three groups of oral administration was y=942.28x-2193.9?r=0.9922?,and between C_max?y?and dose?x?of was y=510.71x-997.07?r=0.9947?.The absolute bioavailability was 41.86%.2.After oral administration of 5.2 mg·kg^-1,WSJ-537 was widely distributed in rats,the highest concentration was detected in the small intestine and stomach,followed by liver,lung,kidney and fat.A small amount of WSJ-537 was also found in brain,testis and ovary.3.After oral administration of 5.2 mg·kg^-1 WSJ-537,the proportion of WSJ-537excreted in the form of prototype is accounting for about 0.36%of the total oral administration dosage.The cumulative excretion of prototype drugs from feces was larger than that of urine.Conclusion:1.After oral administration,WSJ-537 showed linear pharmacokinetic behavior in SD rats;WSJ-537 could be quickly absorbed into the blood and reached the highest plasma concentration;the half-life of WSJ-537 was short,the elimination rate of the drug was fast,and the absolute bioavailability was 41.86%.2.After oral administration,the concentration of WSJ-537 in small intestine was the highest in SD rats,which might be the main absorption site of WSJ-537;the concentration of WSJ-537in stomach,liver,lung and kidney was kind of high;WSJ-537 had strong lipophilicity,therefore there was drug distribution in fat;WSJ-537 could pass through the blood-brain barrier;there was drug distribution in reproductive organs,and the concentration of drug in testis was higher than that in ovary.3.After oral administration,the proportion of prototype WSJ-537 excreted out of body is pretty small,accounting for about 0.36%of the total oral administration dosage,which inferred that after WSJ-537 enters into the organism,it will likely be transformed into metabolites and then excreted,and biotransformation might be the main eliminationway for WSJ-537 in vivo.