Abstract: This study was aimed to investigate the effects of six Schisandra lignans of Wuzhi tablet (WZ, a preparation of ethanol extract of Schisandra sphenanthera) on the pharmacokinetic process of digoxin (DG, a classical P-gp substrate) after intravenous and oral administration in rats. The effect of Schisandra lignans on the transportion of DG in Caco-2 cells was further elucidated. Our data showed that the plasma concentrations of DG were increased to different extent following co-administration of schisandrin A, schisandrin B, schisandrol B and schisantherin A, respectively. Schisandrol B showed the most potent effect among the six lignans. However, schisandrin C and schisandrol A showed little effect on pharmacokinetic of DG. Schisandrol B led to 99.0% (P < 0.05) and 109.2% (P < 0.05) increase in the AUC after orally or intravenously administered of DG, suggesting that co-administration of schisandrol B induced a more potent effect on increasing hepatic bioavailability of DG than that of intestinal. Furthermore, in vitro transport experiment showed that schisandrin A, schisandrin B, schisandrol B and schisantherin A inhibited P-gp-mediated efflux of DG, suggested that these lignans inhibited the P-gp-mediated efflux of DG. In conclusion, the exposure of DG in rats was increased when co-administered with Schisandra lignans, and schisandrol B showed the strongest effect. The dramatic increase in oral bioavailability of digoxin in the presence of schisandrol B may be due to the inhibition of hepatic/renal P-gp activity.