ABSTRACT
Background: Coptidis rhizoma extracts (CREs) have been used widely for their anti-diabetic and anti-microbial activities, and berberine/jatrorrhizine/coptisine/palmatine are the primary bioactive components. Although guidelines have adopted content analyses of these components as a quality control method for CREs, it is difficult to differentiate the CREs from different sources using this method because of the lack of indications for their related pharmacological activities. Purpose: To explore the effect of CREs (CREA/CREB/CREC) with different compositions of major components on the gut microbiota and blood glucose levels in db/db mice. Methods: Degradation of berberine/jatrorrhizine/coptisine/palmatine from CREA/CREB/CREC in rat/mouse intestinal contents and their impact on nine common gastrointestinal bacteria were investigated. In addition, the effects of oral administration of CREA/CREB/CREC for 2 weeks on the gut microbiota and blood glucose levels in db/db mice were monitored via insulin/glucose tolerance test (ITT/GTT), insulin concentration, homeostatic model assessment of insulin resistance and fecal 16S rRNA sequencing. Results and Conclusion: The total amount of berberine/jatrorrhizine/coptisine/palmatine was highest in CREA. Clostridium perfringens was strongly inhibited by all three CREs, with CREA demonstrating the most significant inhibitory effects on minimum inhibitory concentration, time-kill kinetics, and ATP production. In db/db mice, CREA resulted in the most significant decrease in ITT/GTT and depicted different changes in the microbiota from CREB/CREC. Thus, CREs with different compositions of berberine/jatrorrhizine/coptisine/palmatine differed in terms of time-kill kinetics and ATP production assays on C. perfringens. CREA revealed the potent bacterial inhibitory effects and glucose-lowering activity.
ABSTRACT
AIMS: Considering the potential oral administration sequences and role of microbiota for metformin (MET) and berberine (BBR) during anti-diabetic treatments, the current study aimed to investigate the pharmacokinetic interactions between MET and BBR in rats after oral administration at different sequences and impacts of microbiota on such interactions. MAIN METHODS: Sprague-Dawley rats were divided into five groups as per what was orally administered to them: MET (G1)/BBR (G2) at 200â¯mg/kg, BBR 2-hour (h) after dosing MET (G3), MET 2-h after dosing BBR (G4) or MET with BBR at the same time (G5) followed by monitoring their pharmacokinetic profiles. Further in vitro incubations mimicking the above five treatments in rat intestinal content (G1R-G5R), human fecalase (G1H-G5H) and selected bacteria (G1B-G5B) were conducted for both MET and BBR (10⯵g/ml for G1R/H-G5R/H and 50⯵M for G1B-G5B) up to 24-h. Concentrations of MET and BBR were analyzed by LC/MS/MS. KEY FINDINGS: Although BBR was barely measurable in vivo, it significantly increased systemic exposure of MET in G3/G4. Consistent with pharmacokinetic findings, sequential in vitro incubations of MET and BBR in both rat intestinal content and human fecalase demonstrated significant increase on MET persisted after 24-h incubation in G3R/H & G4R/H. Moreover, post-dose (G3B) and pre-dose (G4B) of BBR decreased the MET degradation significantly in most selected bacteria. SIGNIFICANCE: Our finding for the first time demonstrated the significant effect of sequential co-administration of BBR and MET on their pharmacokinetic interactions, which could be related to their microbiota mediated metabolisms in gastrointestinal tract (GI).
