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Scutellarin is the major and active constituent of Dengzhan Xixin Injection (DZXX), a traditional Chinese medicine prepared from the aqueous extract of Erigeron breviscapus and widely used for the treatment of various cerebrovascular diseases in clinic. In present study, the possible pharmacokinetic differences of scutellarin after intravenous administration of scutellarin alone or DZXX were explored. Additional, the potential roles of β‐glucuronidase (GLU) and OATP2B1 in drug–drug interaction (DDI) between scutellarin and constituents of DZXX were further evaluated in vitro. The plasma concentration, urinary and biliary excretion of scutellarin in rats after administration of DZXX, were significantly higher than those received scutellarin, while pharmacokinetic profile of Apigenin 7‐O‐glucuronide (AG) in rats was similar no matter AG or DZXX group. Furthermore, higher concentration in brain and plasma, however, lower level of scutellarin in intestine were observed after intravenous administration of DZXX. Finally, AG and caffeoylquinic acid esters were found to significantly inhibit GLU and OATP2B1 in vitro, which might explain, at least in part, the pharmacokinetic DDI between scutellarin and other chemical constituents in DZXX. The findings provided deep insight into the prescription‐formulating principle in DZXX for treating the cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Abstract Dicaffeoylquinic acids (DCQAs) are widely distributed in daily food and herb medicine (such as Dengzhanxiyin injection) with multiple health benefits and pharmacological activities. However, drug-drug Interactions (DDIs) between DCQAs and possible concomitant drugs were not fully understood in clinic. The purpose of present study was to investigate the role of organic anion transporters (OATs) in the transport of DCQAs and to explore the potential clinical DDIs using in vitro transporter assays. Uptake study using hOAT1/hOAT3-transfected HEK293 cells revealed that none of DCQAs was OAT1 substrate, while 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA were substrates of OAT3 with Km values of 119.7 ± 28.8, 269.3 ± 129.5 and 53.2 ± 32.1 μM, respectively. The docking analysis revealed that 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA were effectively embedded in the active site of OAT3 and fitted well with the cavity in three-dimensional space. Moreover, the classical substrates/inhibitors of OAT decreased the accumulation of 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA in kidney slices, suggesting potential DDI risks with co-administration of substrate drugs of OAT. In fact, antivirals, antibiotics, neuroprotective agents, and PPIs (proton pump inhibitors) all showed varying degrees of inhibition of OAT3-mediated uptake of 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA in vitro. For cefaclor, ceftizoxime, pantoprazole, and zidovudine, in particular, their IC 50 values were <10 times the maximal free plasma concentration, indicating potential clinically relevant DDIs when used together with DCQAs. These findings provided useful information for the prediction of DDIs between DCQAs and OAT3 inhibitors, and rational application of herbal medicines containing DCQAs in clinic. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]