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

Abstract

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.

Rotundic Acid Protects against Metabolic Disturbance and Improves Gut Microbiota in Type 2 Diabetes Rats

“…Triterpene is an important ingredient of medicinal and food plant, which commonly has extensive bioactivities but low bioavailability [28]. Moreover, a previous report showed that RA could be metabolized into bioactive metabolites by microbial metabolism [12,13]. Therefore, we hypothesized that the protective effects of RA against T2D were partly explained by its ability to improve gut microbiota and 16 s rRNA gene amplification and sequencing were conducted in T2D rats.…”

“…On the other hand, microbial metabolism is capable of metabolizing RA into bioactive metabolites [12]. Due to the chemical complexity, RA may be hard to be absorbed in the small intestine and then pile up in the lumen of the large intestine in the intact form [13]. We hypothesized that RA could improve gut microbiota to protect against metabolic disturbance in T2D.…”

Absolute bioavailability, dose proportionality, and tissue distribution of rotundic acid in rats based on validated LC-QqQ-MS/MS method

“…1 B). The ion transition of RA selected in this assay was different from that previously reported [ 34 , 35 ], where the mass transition chosen for quantitation was m/z 487.34 → 469.33 for RA. The difference in the ion pair selected may be due to disparity in instruments.…”

“…Therefore, etofesalamide was selected as the IS. In previous studies [ [33] , [34] , [35] ], digoxin and tanshinone IIA were chosen as IS, respectively.…”

Rapid Identification of the Chemical Components of Ilex rotunda Thunb Using UPLC-Q-TOF-MS/MS

“…Modern pharmacological studies have shown that IRC extract has several effects such as reducing coronary artery flow, slowing heart rate, improving hypoxia tolerance, and antiarrhythmic effects. Notwithstanding that it is often used in the treatment of cardiovascular diseases in a clinical setting, the active components and mechanism of action of IRC remain unclear [1][2][3].…”