Significant pharmacokinetic differences of berberine are attributable to variations in gut microbiota between Africans and Chinese

Abstract

We investigated the influence of gut microbiotal metabolism on the pharmacokinetics of berberine in healthy male Africans and Chinese. The Cmax and AUC in the Africans were 2.67-fold and 2.0-fold higher than the Chinese, respectively. Microbiotal compositions by 16S rRNA pyrosequencing showed higher abundance of the genera Prevotella, Bacteroides, and Megamonas (34.22, 13.88, and 10.68%, respectively) in the Chinese than the Africans (30.08, 9.43, and 0.48%, respectively). Scatter plot showed a strong negative correlation between the microbiotal abundance and the berberine AUC, especially for the genus Prevotella (r = -0.813) and its species. A more extensive metabolism was observed in Chinese with 1.83-fold higher metabolites, possibly contributing to the lower AUC than the Africans. In conclusion, significant PK differences of berberine were observed between Africans and Chinese, which is partly attributable to variations in gut microbiota and its corresponding metabolic capacity.

Figure 1. Plasma concentration-time curves and areas under the curve.

Results are shown for the plasma concentration-time curve of berberine (Panel A; values are represented as means ± SEM). Panel B shows the box plot of areas under the curve in 12 hours for 10 Africans and 10 Chinese (***represents difference with a p value < 0.001). P values are analyzed based on student’s t-test.

Figure 2. Intestinal microbiota communities of Chinese and Africans.

(A) The relative abundance map for the bacteria in the stool were analyzed by 16S rRNA pyrosequencing. Feces were collected from all the participants enrolled in the pharmacokinetic study. The values were represented as the average abundance of each genus in the metagenomics test (percentage). (B) Heatmap and represented bacterial taxa information (species, genus, family and phylum) of 81 significantly changed OTUs between Africans and Chinese.

Figure 3

The correlation between areas under the curve (AUCs) and abundances of intestinal genus Prevotella (A), Bacteroides (B), Faecalibacterium (C), and Megamonas (D). Green plots represent Chinese participants, and blue plots represent African volunteers.

Figure 4. Intestinal metabolism of berberine.

Results are shown for the concentrations of berberine left and 6 major metabolites generated in the medium after anaerobic incubation with intestinal microbiota for 48 hours at a concentration of 1 μmol/L in vitro. The intestinal microbiota was randomly collected from 3 Africans and 3 Chinese participated in the pharmacokinetic analysis. Concentrations were represented as means ± SEM. The concentrations of dihydroberberine (M6) were observed to be equal between races. *p value < 0.05; and **p value < 0.01. P values are based on Student’s t-test analyses. M1, Berberrubine; M2, Thalifendine; M3, Columbamine; M4, Demethyleneberberine; M5, Jatrorrhizine; M6, Dihydroberberine.