Effects of Gut Microbiota and Ingredient-Ingredient Interaction on the Pharmacokinetic Properties of Rotundic Acid and Pedunculoside.

Rotundic acid and pedunculoside are the most abundant constituents in Ilicis Rotundae Cortex, and possess lipid-lowering activity. In this study, we evaluated the pharmacokinetic interactions of rotundic acid with pedunculoside and other ingredients from Ilicis Rotundae Cortex with rotundic acid and pedunculoside, and preliminarily investigated the effects of gut microbiota on their pharmacokinetics using a pseudo-germ-free rat model. After a single oral administration of each monomer, a monomer mixture, and Ilicis Rotundae Cortex extract to the conventional and pseudo-germ-free rats, rotundic acid and pedunculoside were quantified in plasma by an UPLC/Q-TOF-MS/MS method. The systemic exposure (maximum plasma concentration and area under concentration-time curve) of two analytes in conventional rats were increased in an approximately dose-dependent manner. Oral administration of rotundic acid and pedunculoside in the forms of a monomer mixture and Ilicis Rotundae Cortex extract to the conventional rats significantly decreased the systemic exposure compared with the monomer groups, which demonstrated the existence of significant pharmacokinetic interactions. The pseudo-germ-free rats were prepared by nonabsorbable antibiotic treatment, and the systemic exposure of two analytes were significantly decreased and most of the "time to reach the maximum" values were delayed in comparison to conventional rats, therefore gut microbiota might serve as an efficient absorption promoter. These results provide a scientific basis for the clinical application of the two bioactive constituents and Ilicis Rotundae Cortex.