The Main Influencing Factors Of The Distribution Of Timosaponin B-II Hepatobiliary

Timosaponin B-II(TB-2),one of the major steroid glycosides isolated from Anemarrhenaasphodeloides,is a promising drug candidate because of multiple pharmacological activities;however,the pharmacokinetic and metabolic profiling of this substance remain obscure.In this study,rosuvastatin,a well-known drug for dyslipidemia,was chosen as a probe to investigate the potential DDI with TB-2 and identify cellular kinetics of TB-2.Furthermore,rosuvastatin is the substrate of OATP1B1/1B3 BCRP,and MRP2,and the major elimination pathway of rosuvastatin is biliary excretion.On the basis on these,we found that TB-2 could significantly increase the concentration of rosuvastatin in rat plasma(Cmax = 41.5 ng/ml to 102.6 ng/ml;AUC = 210.6 to 398.3 h ng/ml)and decrease its biliary excretion amount(1589.8 ± 61.6 ng to 884.8 ± 25.8ng)in a dose-dependent manner.The inhibitory effect of TB-2 on the biliary excretion of rosuvastatin was confirmed in sandwich-cultured rat hepatocytes(SCRH).Biliary excretion index(BEI)decreased from 42.8%to 18.7%.Based on these data,results showed that TB-2 could be a strong substrate of organic anion-transporting polypeptide 1B1/3(OATP1B1/1B3)in OATP1B1/1B3 transfected cells.Observing SCRH,we found that TB-2 biliary excretion was regulated by breast cancer resistance protein(BCRP)and multidrug resistance protein(MRP2).In contrast to previous results,our findings showed that the metabolism of TB-2 could not be observed in S9,liver microsomes,or primary hepatocytes.However,BEI of TB-2 could reach 40%to 60%and distinct enterohepatic circulation could be observed in vivo.These results indicated that biliary excretion,not metabolism was the major elimination pathway of TB-2.Furthermore,essential influx/efflux transporters contributed considerably to hepatobiliary disposition.