title: Metabolism and pharmacokinetics of 8-hydroxypiperidinylmethyl-baicalein (BA-j) as a novel selective CDK1 inhibitor in monkey.
abstract: Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. 8-Hydroxypiperidinemethyl-baicalein (BA-j) is a Mannich base derivative of baicalein (BA) isolated from Scutellaria baicalensis, as a novel selective CDK1 inhibitor. 12 metabolites of BA-j in the monkey urine were identified by LC-MS-MS and (1)H NMR. The major metabolic pathways of BA-j, by capturing oxygen free radicals ((.)O2(-)) and releasing peroxides (H2O2), are degraded into active intermediate metabolite dihydroflavonol, then into main metabolite M179 by Shiff reaction, second metabolite M264 by sulfation, trace amount of metabolite M559 by glucuronidation UGT1A9, and without metabolism by CYP3A4. The metabolic process of BA-j by regulating intracellular reactive oxygen species (ROS) was related with BA-j selectively inducing apoptosis in cancer cells. Pharmacokinetics of 10mg/kg oral BA-j in monkey by HPLC-UV was best fitted to a two-compartment open model, with t1/2(β) of 4.2h, Cmax 25.4μM at 2h, and Vd 12.6L, meaning the drug distributing widely in body fluids with no special selectivity to certain tissues, and being able to permeate through the blood-brain barrier. The protein binding rate of BA-j was 91.8%. BA-j has excellent druggability for oral administration or injection, and it may be developed into a novel anti-cancer drug as a selective CDK1 inhibitor.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China. Electronic address: zhangsx56@aliyun.com.
authors.forename: Shi-Xuan
authors.initials: SX
authors.lastname: Zhang
authors.affiliation: College of Vocational and Technical, Dalian University, Dalian, Liaoning, China.
authors.forename: Xiu-Lan
authors.initials: XL
authors.lastname: Ju
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Ai-Yun
authors.initials: AY
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Li
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D044950:Flavanones / Q000378:metabolism / Q000493:pharmacokinetics*; D047309:Flavones / Q000378:metabolism / Q000493:pharmacokinetics*; D005609:Free Radicals / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D010880:Piperidines / Q000378:metabolism / Q000493:pharmacokinetics*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D031364:Scutellaria baicalensis / Q000737:chemistry*; D053719:Tandem Mass Spectrometry
chemical_list: C000606484:8-hydroxypiperidinylmethylbaicalein; D044950:Flavanones; D047309:Flavones; D005609:Free Radicals; D010880:Piperidines; D017382:Reactive Oxygen Species; C006680:baicalein; D006861:Hydrogen Peroxide; D016203:CDC2 Protein Kinase
keywords: 8-Hydroxypiperidine-methyl-baicalein (BA-j); Anti-cancer drug; Baicalein (BA); Peroxides (H(2)O(2)); Pharmacokinetics CDK1 inhibitor