The Preclinical Pharmacokinetic Study Of A Novel Anti-Alzheimer's Disease Candidate Compound JCC-02

Objective:A novel anti-Alzheimer's candidate compound,JCC-02,has been developed according to the structure of Memantine.It has been shown to be slightly more potent than Memantine.In this study,a method for the determination of JCC-02 in biological samples was developed and applied to its pharmacokinetics,tissue distribution and excretion study in rats.Methods:1.A liquid chromatography-tandem mass spectrometry?LC-MS/MS?method was developed to determine the concentration of JCC-02 in rat plasma to investigate its pharmacokinetic behavior.This validated method was successfully applied to JCC-02pharmacokinetic study in rats after oral administration of low(0.7 mg·kg^-1),medium(2mg·kg^-1)and high(6 mg·kg^-1)concentration,tail intravenous administration(2 mg·kg^-1).2.A liquid chromatography-tandem mass spectrometry?LC-MS/MS?method was developed to determine the concentration of JCC-02 in rat tissues to investigate its distribution character in organs after oral administration of JCC-02(2 mg·kg^-1)and tail intravenous administration(2 mg·kg^-1).3.A liquid chromatography-tandem mass spectrometry?LC-MS/MS?method was developed to determine the concentration of JCC-02 in rat urineand faeces to investigate its excretion character after oral administration of JCC-02(2 mg·kg^-1).Results:1.The linear equation between AUC_0-??y?and dosage?x?was y=67.71x+6.210?r=0.9982?.The linear equation between C_max?y?and dosage?x?was y=9.428x+19.99?r=0.9500?.T_max in these three groups were all less than 1 h and t_1/2/2 were longer than 6 h.Clearance?CL?value lower than nomal liver blood flow in the rat and the volume of distribution?Vd?higher than the total fluid volume in the rat.The absolute bioavailability of JCC-02 oral administration was obtained as?14.61±5.81?%.2.The concentration of JCC-02 in stomach,large intestine and small intestine of the oral administration group was significantly higher than that of the intravenous administration group.Besides,the concentration in the small intestine was the highest.Concentration of JCC-02 in fat and liver was relatively high.It has also been detected in the brain and reproductive organs.3.After oral administration,the cumulative excretion of JCC-02 in faeces in the form of the prototypical drug was significantly greater than that in urine.The cumulative excretion of the drug increased slowly after 12 hours of administration.Conclusion:1.Since both r values were larger than 0.9,JCC-02 showed linear pharmacokinetics in rats.JCC-02 could be absorbed into blood circulation rapidly.JCC-02 had a long half-life in rats.It might be the result of the low CL and the high Vd.The absolute bioavailability of JCC-02 oral administration was a little poor.2.After oral administration,JCC-02 was first widely distributed in the digestive organs.It was likely that the small intestine was the main absorption site for oral administration and the liver was the main organ for drug metabolism.Drug distribution in the brain suggested that JCC-02 could cross the blood-brain barrier?BBB?.The drug concentration in reproductive organs,especially ovaries,was not low in both groups.Therefore,the influence of drugs on reproductive organs should be considered in future studies on pharmacodynamics and toxicology.3.Since the proportion of JCC-02 excreted in the form of prototype drugs was relatively small,accounting for about 12%of the total oral dose,it could be inferred that after oral administration,JCC-02 would be converted into metabolites and then excreted out of the body.Biological transformation may be the main way for its elimination.