The Pharmacokinetics Of Bile Acid Coupled With Berberine Derivatives A4 And B4

BBR is suggested to be poorly absorbed across the gut after oral administration,and has undesirable first-pass effects,poor tolerance.Patients have to be treated with multiple doses of BBR to overcome its low efficiency.These disadvantages generally frustrate and preclude its clinical application.Bile acid can transport drugs by enterohepatic circulation.Drugs coupled with bile acid by chemical method.The new derivatives can target the liver and intestinal in contrast to low others distribution,and they play a key role in curing the liver and intestinal disease.Meanwhile,bile acid is the endogenous substance.It possessed favorable biological compatibility compared with other exogenous carrier.Therefore,bile acid as carrier can achieve the target to liver and intestinal,reduce the side-effect,and improve the uptake and bioavailability.In an attempt to improve the targeting ability,liposolubility,bioactivity and bioavailability of berberine(BBR),based on lots of references and our previous experiment,A4 and B4 were synthesized by nucleophilic substitution,amidatio and esterification at C-9 of BBR with fast reaction ratio and high production.The dissertation studied the binding interactions between bovine serum albumin(BSA)and the berberine derivatives A4,B4,and berberine(BBR)in vitro,oral bioavailability,pharmacokinetics,and tissue distribution of A4,B4,and BBR in vivo.The results indicated that the fluorescence of BSA was strongly quenched by the binding of BBR derivatives to BSA.The quenching mechanism of the BBR derivatives was static according to the Stern-Volmer equation.The thermodynamic parameters implied that the interaction process was spontaneous and electrostatic interactions played an important role.According to Forster’s non-radioactive energy transfer theory,the binding distances between BSA and A4,B4,and BBR,were 3.38 nm,3.27 nm,and 3.53 nm,respectively.The binding ability of B4 to BSA is the strongest among the tested BBR derivatives.Site marker competitive experiments indicated that the binding of BBR derivatives to BSA primarily took place at site II.Our data demonstrate that these fluorescence-quenching methods can be used to rapidly and sensitively determine the binding interactions between BBR derivatives and BSA.A rapid and simple liquid chromatography tandem mass spectrometry method was established.This method is used as quantified the concentration of berberine compounds in plasma and tissue distribution.The analysis method,included specificity,linearity,precision and accuracy,the matrix effect and the recovery rate of extraction and stability was validated.After oral administration of berberine compounds(25μmol/kg,50μmol/kg,70μmol/kg),the pharmacokinetics parameters were calculated.B4 was absorbed in vivo for longer time than berberine,but,A4 is the opposite of B4.B4 abundantly gathered in intestinal tissue.Intestinal and liver act as the main organs to absorb and metabolize.The dissertation found that B4 was appropriate to cure intestinal cancer resulted from high oral bioavailability.All of results lay a foundation for further research and clinical evaluation of B4.