Metabolism and pharmacokinetics of 8-hydroxypiperidinylmethyl-baicalein (BA-j) as a novel selective CDK1 inhibitor in monkey

• Published in: Fitoterapia 2015-12, Vol.107, p.36-43
• Main Authors: Guo, Hong-min, Sun, Yu-ming, Zhang, Shi-xuan, Ju, Xiu-lan, Xie, Ai-yun, Li, Jing, Zou, Liang, Sun, Xiao-dan, Li, Hai-liang, Zheng, Yang
• Format: Article
• Language: English
• Subjects: 8-Hydroxypiperidine-methyl-baicalein (BA-j); Anti-cancer drug; antineoplastic agents; apoptosis; Baicalein (BA); biochemical pathways; blood-brain barrier; body fluids; cell proliferation; cyclin-dependent kinase; free radicals; high performance liquid chromatography; hydrogen peroxide; medicinal plants; metabolites; monkeys; neoplasm cells; neoplasms; nuclear magnetic resonance spectroscopy; oral administration; Peroxides (H2O2); pharmacokinetics; Pharmacokinetics CDK1 inhibitor; protein binding; Scutellaria baicalensis; superoxide anion; tandem mass spectrometry; urine
• ISSN: 0367-326X
• DOI: 10.1016/j.fitote.2015.10.001

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 1H 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. [Display omitted]