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

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(ß) 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.

Combination coating of chitosan and anti-CD34 antibody applied on sirolimus-eluting stents can promote endothelialization while reducing neointimal formation.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) capture technology improves endothelialization rates of sirolimus-eluting stents (SES), but the problem of delayed re-endothelialization, as well as endothelial dysfunction, has still not been overcome. Therefore, we investigated whether the combination coating of hyaluronan-chitosan (HC) and anti-CD34 antibody applied on an SES (HCASES) can promote endothelialization, while reducing neointimal formation and inflammation. METHODS: Sirolimus-eluting stents(SES), anti-CD34 antibody stents (GS) and HC-anti-CD34 antibody combined with sirolimus-eluting stents (HCASES) were deployed in 54 normal porcine arteries and harvested for scanning electron microscopy (SEM) and histological analysis. The ratio of endothelial coverage above the stents was evaluated by SEM analysis at 7, 14 and 28 days. The percentage of in-stent stenosis was histologically analyzed at 14 and 28 days. RESULTS: SEM analysis at 7 days showed that endothelial strut coverage was increased in the HCASES group (68±7%) compared with that in the SES group (31±4%, p=0.02). At 14 days, stent surface endothelialization, evaluated by SEM, showed a significantly higher extent of endothelial coverage above struts in the GS (95 ± 2%) and the HCASES groups (87±4%) compared with that in the SES group (51±6%, p=0.02). Histological examination showed that the percentage of stenosis in the HCASES group was not significantly different to that of the SES and GS groups (both p> 0.05). At 28 days, there was no difference in the rates of endothelial coverage between the HCASES and GS groups. The HCASES group showed less stenosis than that in the GS group (P < 0.05), but it was not significantly different from the SES group (P=0.068). CONCLUSIONS: SEM and histology demonstrated that HCASESs can promote re-endothelialization while enhancing antiproliferative effects.