title: High fat diet aggravates the nephrotoxicity of berberrubine by influencing on its pharmacokinetic profile.
abstract: 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.
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Runbin
authors.initials: R
authors.lastname: Sun
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhen
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jiahua
authors.initials: J
authors.lastname: Guo
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Geng
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jiankun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Feng
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Fei
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Pharmacology, Clinical Research Institute of Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210009, PR China.
authors.forename: Xuanxuan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Pharmacy School at Yantai University, Yantai 264005, PR China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Pharmacy School at Yantai University, Yantai 264005, PR China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Fu
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: jiyea@cpu.edu.cn.
authors.forename: Jiye
authors.initials: J
authors.lastname: Aa
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D001599:Berberine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity / Q000652:urine; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007677:Kidney Function Tests; D008055:Lipids / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D051437:Renal Insufficiency / Q000139:chemically induced / Q000209:etiology* / Q000652:urine
chemical_list: D019440:Anti-Obesity Agents; D008055:Lipids; D001599:Berberine; C115958:berberrubine
keywords: Berberine; Berberrubine; HFD; Nephrotoxicity; Pharmacokinetic