1. Academic Validation
  2. Microdialysis combined with RRLC-MS/MS for the pharmacokinetics of two major alkaloids of Bi qi capsule and the potential roles of P-gp and BCRP on their penetration

Microdialysis combined with RRLC-MS/MS for the pharmacokinetics of two major alkaloids of Bi qi capsule and the potential roles of P-gp and BCRP on their penetration

  • J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Aug 15;1092:72-81. doi: 10.1016/j.jchromb.2018.05.048.
Tiankun Ren 1 Menglin Li 2 Hao Zheng 3 Wenwei Liu 4 Jinlan Zhang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: rentiankun@imm.ac.cn.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: menglin@imm.ac.cn.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: zhengh@imm.ac.cn.
  • 4 Tianjin Darentang Jingwanhong Pharmaceutical CO., Ltd., Tianjin 300112, China.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: zhjl@imm.ac.cn.
Abstract

Bi qi capsule (BQC) is a traditional Chinese medicine prescription that is clinically used for the treatment of rheumatoid arthritis. Strychnine and brucine, as two typical kinds of Alkaloids, are the primary active and neurotoxic constituents of BQC. In this study, a sensitive and reliable rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) quantitative method was used to determine the concentrations of brucine and strychnine in rat brain and blood dialysates. The blood-brain barrier (BBB) penetration of free brucine and strychnine and their pharmacokinetic characteristics were investigated by the validated RRLC-MS/MS method coupled with in vivo microdialysis for the first time. The dialysate brain-blood AUC ratios of brucine were 0.098, 0.44 and 0.40 respectively at 0.4, 0.8 and 1.6 g kg-1 doses of BQC, and the dialysate brain-blood AUC ratios of strychnine were 0.20, 1.25 and 2.06 respectively at 0.4, 0.8 and 1.6 g kg-1 doses of BQC. The high brain-blood AUC ratios of brucine and strychnine were observed in medium and high dose groups of BQC. In addition, the effects of P-glycoprotein (P-gp) and breast Cancer resistance protein (BCRP) on brucine and strychnine across BBB were also studied using the above method as well as molecular docking. The results prompted that brucine was the substrate of P-gp, and strychnine might be the inhibitor of P-gp. Brucine and strychnine showed high brain penetration, so it is very important to well control the clinic dosage of BQC and manufactory quality for avoiding the side effects and obtaining good therapeutic efficacy. Our study could be further used in investigating BBB penetration for other drugs caused neurotoxicity.

Keywords

Bi qi capsule; Brucine; Microdialysis; Pharmacokinetics; RRLC-MS/MS; Strychnine.

Figures
Products