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The influence of broad-spectrum antibiotics on the pharmacokinetics and biotransformation of major constituents of Shaoyao-Gancao decoction (SGD) in rats was investigated.The pharmacokinetic behaviors of paeoniflorin (PF),albiflorin (AF),liquiritin (LT),isoliquiritin (ILT),liquiritin apioside (LA),isoliquiritin apioside (ILA),and glycyrrhizic acid (GL),seven major constituents of SGD,as well as glycyrrhetinic acid (GA),a major metabolite of GL,were analyzed.A 1-week pretreatment with broad-spectrum antibiotics (ampicillin,metronidazole,neomycin,1 g L-1;and vancomycin,0.5 g L-1) via drinking water reduced plasma exposure of the major constituents.The AUC0-24 h of PF and LT was significantly decreased by 28.7％ and 33.8％ (P ＜ 0.05 and P ＜ 0.005),respectively.Although the differences were not statistically significant,the AUC0-24 h of AF,ILT,LA,ILA,and GL was decreased by 31.4％,50.9％,16.9％,44.1％,and 37.0％,respectively,compared with the control group.In addition,the plasma GA exposure in the antibioticpretreated group was significantly lower (P ＜ 0.005) than the control group.The in vitro stability of the major constituents of SGD in the rat intestinal contents with or without broad-spectrum antibiotics was also investigated.The major constituents were comparatively stable in the rat duodenum contents,and the biotransformation of GL mainly occurred in the rat colon contents.In summary,broad-spectrum antibiotics suppressed the absorption of the major constituents of SGD and significantly inhibited the biotransformation of GL to GA by suppressing the colon microbiota.The results indicated a potential clinical drug-drug interaction (DDI) when SGD was administered with broad-spectrum antibiotics.