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ShenMai,an intravenous injection prepared from steamed Panax ginseng roots (Hongshen) and Ophiopogon japonicus roots (Maidong),is used as an add-on therapy for coronary artery disease and cancer;saponins are its bioactive constituents.Since many saponins inhibit human organic anion-transporting polypeptides (OATP)1B,this investigation determined the inhibition potencies of circulating ShenMai saponins on the transporters and the joint potential of these compounds for ShenMai-drug interaction.Circulating saponins and their pharmacokinetics were characterized in rats receiving a 30-min infusion of ShenMai at 10 mL/kg.Inhibition of human OATP1B1/1B3 and rat Oatp1b2 by the individual saponins was investigated in vitro;the compounds’ joint inhibition was also assessed in vitro and the data was processed using the Chou-Talalay method.Plasma protein binding was assessed by equilibrium dialysis.Altogether,49 saponins in ShenMai were characterized and graded into:10-100 μmol/day (compound doses from ShenMai;7 compounds),1-10 μmol/day (17 compounds),and ＜1 μmol/day (25 compounds,including Maidong ophiopogonins).After dosing,circulating saponins were protopanaxadiol-type ginsenosides Rb1,Rb2,Rc,Rd,Ra1,Rg3,Ra2,and Ra3,protopanaxatriol-type ginsenosides Rg1,Re,Rg2,and Rf,and ginsenoside Ro.The protopanaxadiol-type ginsenosides exhibited maximum plasma concentrations of 2.1-46.6 μmol/L,plasma unbound fractions of 0.4-1.0％ and terminal half-lives of 15.6-28.5 h (ginsenoside Rg3,1.9 h),while the other ginsenosides exhibited 0.1-7.7 μmol/L,20.8-99.2％,and 0.2-0.5 h,respectively.The protopanaxadiol-type ginsenosides,ginsenosides without any sugar attachment at C-20 (except ginsenoside Rf),and ginsenoside Ro inhibited OATP1B3 more potently (ICs0,0.2-3.5 μmol/L) than the other ginsenosides (≥22.6 μmol/L).Inhibition of OATP1B1 by ginsenosides was less potent than OATP1B3 inhibition.Ginsenosides Rb1,Rb2,Rc,Rd,Ro,Ra1,Re,and Rg2 likely contribute the major part of OATP1B3-mediated ShenMai-drug interaction potential,in an additive and time-related manner.