High fat diet aggravates the nephrotoxicity of berberrubine by influencing on its pharmacokinetic profile

• Berberrubine exerted a stronger lipid-lowering effect than berberine in vivo.
• Berberrubine showed a specific nephrotoxicity especially in mice fed with HFD.
• HFD aggravated the nephrotoxicity by influencing on the pharmacokinetic profile.
• In vitro assessment showed berberrubine could produce a toxic effect on renal cells.
• The primary metabolite of berberrubine did not show any obvious toxicity.

Berberrubine (BRB), the active metabolite of berberine (BBR), possesses various pharmacological activities. In this study, we found BRB showed not only a stronger lipid-lowering effect than berberine but also a specific nephrotoxicity in mice fed with high fat diet (HFD). To explore the underlying mechanism, the pharmacokinetics of BRB were evaluated. There was a greater in vivo exposure of BRB in C57BL/6J mice fed with HFD than with routine chows, in terms of Cmax, AUC0-t, levels of BRB in kidney and urinary excretion. Moreover, in vitro assessment clearly showed BRB had a toxic effect on renal cell lines, while the primary metabolite, berberrubine-9-O-β-d-glucuronide (BRBG), did not show any obvious toxicity. These results suggested HFD aggravated BRB-induced nephrotoxicity by promoting the in vivo exposure of BRB especially in urine and kidney. Although our previous study indicated BRB could be metabolized into BRBG, BRBG did not show any obvious toxicity in vitro.

Figure optionsDownload as PowerPoint slide