Effects of P-glycoprotein on the intestine and blood-brain barrier transport of YZG-331, a promising sedative-hypnotic compound.

YZG-331 is a synthetic adenosine analogue which exhibits the sedative and hypnotic effects by binding to the adenosine receptor. The present study was designed to investigate the effects of P-glycoprotein (P-gp) on the intestine and brain distribution of YZG-331 in vitro and in vivo as well as related binding mechanisms. The activity of P-gp ATPase was both induced by YZG-331 and verapamil, a typical P-gp inhibitor, but affinity of YZG-331 for P-gp was lower than that of verapamil. The docking analyses further elucidated the binding relationship of YZG-331 and P-gp. The directional transport of YZG-331 was disappeared in Caco-2 and MDCK-MDR1 cells when the P-gp activity was blocked. However, the penetration of digoxin, a P-gp known substrate, was not change in MDCK-MDR1 cells along with YZG-331. In the everted intestinal sac model, the influx of YZG-331 was significantly reduced in the presence of verapamil in all the segments except for the colon. In the in situ and in vivo study, the brain exposure of YZG-331 was promoted after co-administered of verapamil. Furthermore, the Kp value changed from 0.03 to 0.05 after drug combination. Taken together, these results indicated that YZG-331 is a substrate but may not an inhibitor of P-gp. The intestine and brain permeability of YZG-331 can be restricted, at least in part, by P-gp. The drug interactions should be awarded when YZG-331 and other P-gp-related drugs used together.