| Candidate compound HDZ126016 is a kinase inhibitor with strong antitumor activity against a variety of human cancers.This is one of National Science and Technology Major Projects for "Major New Drugs Innovation and Develpment(No 2009ZX09103-084)". This project is to study the mechanism of gastrointestinal and oral absorption of the insoluble, hydrophobic drug. Meanwhile, as the basis of prescription design, and filter out the higher bioavailability of the tablet prescription. HDZ216016,as the new drug, Currently there is no related agents on the market at home and abroad, the research of its prescription is the basic premise and guarantee of clinical research and listing, it also have the directive function to the relevant research of oral formulations of insoluble drugs.This article is aimed at studying HDZ126016’s basic biological, physical and chemical properties, so as to provide a reasonable basis for HDZ 126016 tablets, and completing its initial screening of prescription and pharmaceutical research.The subject mainly includes three sections as follows:1:The development of HPLC method for determination of HDZ 126016 and the absorption and transportation of HDZ 126016 across Caco-2 Monolayer Model.First of all, a highly sensitive HPLC method with standard specificity and precision for determination of HDZ 126016 was developed. Then the Caco-2 cell model was used to study the transport of HDZ126026. The results indicted:(1) at low concentrations, HDZ126026’s absorption is a transporter-mediated process. The uptake of HDZ126026 was positively correlated to concentrations of donor solution. This process saturates at high concentrations. (2) Transport of HDZ 126026 across Caco-2 cell monolayers was directional. Papp of Apical to Basolateral was much more than that of Basolateral to Apical with the ratio ranges from 2.36 to 7.58. (3) Sodium azide, the ATP inhibitor, decreased transport of HDZ126026 from AP-BL directions, while increased the other, which indicates transport of HDZ126026 is energy dependent. (4) In the presence of Glucose, the Papp AP-BL increasingly decreased.Via liver microsome experiments we first examined the in vitro metabolism of HDZ126016. The results indicted:HDZ 126016 has a low metabolic activity, and the metabolism of HDZ 126016 has a small species differences.2:Pharmaceutical Study on HDZ 126016Before the prescription study, we determined the candidate compound’s IgP values and solubility in defferent solutions,and developed the test conditions for HDZ126016 tablets.In the prescription study, we have focused on the disintegration and dissolution of our candidate compound to screen and identify the main component of the tablets. Finally, we achieved the best prescription of HDZ126016 tablets via a homogeneous design, and initially identified candidate compound HDZ126016’s prescriptio n and preparation process.3:Pharmacokinetic study of HDZ126016 in rats.The preliminary pharmacokinetic studies have shown:1.The concentration-time curves of p-Ts salt and free base of HDZ126016971 in rats after intravenous injection are consistent with two-compartment model. The elimination phase half-life were 12.40 hours and 8.41 hours, respectively; 2. The metabolic processes of p-Ts salt and free base of HDZ 126016971 in rats after oral administration were consistent with a two-compartment model. The elimination phase half-life of its solution and suspension of tablet prescription 1 were 29.61 hours and 11.59 hours for salt,27.18 hours and 7.08 hours for free base, respectively; peak at 9.50 hours and 4 hours,10.40 hours and 10.0 hours, respectively; peak concentrations were 1771.39ug/L and 605.91ug/L,1458.38ug/L and 511.98ug/L, respectively; the bioavailability were 18.70% and 2.99%,11.30% and 2.78%, respectively; 3. Both p-Ts salt and free base of HDZ 126016971 didn’t influence the pharmacokinetic process. |
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