Pharmacokinetics Research Of 6-Acety-8-Hydroxypiperidinemethyi Chrysin

Hypoxia is an important feature of solid tumor microenvironment, and hypoxia inducing factor la (HIF-la) has become an effective target for inhibitting solid tumors. Chrysin is a natural flavonoid, and the main component in propolis. It has the activity of targeting inhibition of HIF-1?. However, poor solubility and low bioavailability limits the clinical use of Chrysin. Therefore, it is of great significance to conduct structural modification of Chrysin to make medicinal properties more excellent.6-Acety-8-Hydroxypiperidinemethyl Chrysin (CH-j) is a new type of Chrysin Mannich base derivatives of total synthesis by our team.In this paper, the method for intravital CH-j analysis was established and validated by HPLC-UV. Th urine drug concentrations-time curve of Monkey accorded with two compartment model after a single dose oral administration of CH-j (5mg/kg). CH-j Tmax1 1.3h, Cmax1 26.4?M, Tmax2 9h, Cmax2 13.2?M (IC50 6.25?M), phase elimination half-life (T1/2(?)) 6.2h, the area under the curve (AUCo-? 20.4?M*h), apparent volume of distribution Vd 42L with mainly distributing in the whole body fluid. The results suggested that CH-j was easily distributed into tissue cells. So, we speculated that CH-j would be more effective for solid tumors.10 kinds of metabolites of CH-j were identified by LC-MS. The major metabolic pathway in monkeys was speculated that CH-j captured O2-, released H2O2, and formed an active metabolite of flavanone alcohols, further decomposed into major metabolite M179 and M152 and M264 by sulfating oxygenolysis in monkeys. The results suggested that CH-j could effectively avoid the "deeply outside effect", improve bioavailability, and get good pharmacokinetic properties. The catabolism property of CH-j was excellent.The distribution of CH-j in rat tissues was detected after a single oral administration of CH-j (100mg/ml). The results showed that CH-j was widely distributed in tissues/organs. Among which, the highest concentration of CH-j was in stomach, more than 1 time the drug concentration in other tissues. Drug concentrations in tissues were far above that in plasma. The results suggested that CH-j was absorbed mainly in stomach. CH-j was fat-soluble, and would be efficient for solid tumors.The plasma protein binding rate of CH-j was 86% with concentration-independent by the method of equilibrium dialysis, the reversible combination rate of CH-j was 90%. Thus, CH-j was easily distributed into tissues.In conclusion, CH-j had unique pharmacokinetic properties with capturing O2-and releasing H2O2 and a wide tissue distribution. So that CH-j would be more selective for solid tumors with a kind of inhibitor targeting HIF-1?.