Prediction Of Oral Drug Absorption In Humans By Experimental Biopartitioning Micellar Chromatography Indices

Two parts are included in this thesis:one part is about employed biopartitioning micellar chromatography theory forecasts the oral drug absorption in the human body,establish and perfect the BMC predict drug oral absorption mode,compare the current reported of BMC predict oral drug absorption model, validation the ability of BMC system in evaluation of drug membrane transport provide reference for drug design and drug development;the other is about using biopartitioning micellar chromatography forecasts the effective components of chinese herbal medicine rhubarb in the small intestine of rats in vivo intestinal absorption,use biopartitioning micellar chromatography for chromatographic analysis, the capacity factor k as judgment standard,predict main effective components in radix et rhizoma rhei extracts in vivo intestinal absorption in rats,combined with the literature and research work,demonstrate that apply the method of BMC in the field of study chinese herbal medicine has certain feasibility and guiding significance and they are described as follows.With the speedy development of new chemical entities (NCEs), it is of great importance to eliminate the NCEs with poor pharmacokinetic properties early in drug discovery pipeline.Different technologies have emerged that enable rapid screening in vitro for sorting out valuable NCE classes.It is priceless for these technologies for they can save enormous costs and much time and efforts in late development due to poor absorption and/or bioavailability. Biopartitioning micellar chromatography (BMC) is such convenient,rapid and cost-effective tools that use micelles mobile phases of Brij35 and mixture mobilephases of Brij35-SDS under adequate experimental conditions to mimic the drug partitioning process in biological systems and to predict human oral absorption (HOA%). The aims of the present research were to detect whether or not the HOA% can be well predicted by the experimentally determined biopartitioning micellar chromatography capacity factor (kBMC). A negative exponential growth curve model has been obtained by correlating HOA% values withmc of a heterogeneous set of 67 compounds,both shows predictive ability for drugs absorbed by passive diffusion,the usability of the models were validated by the test set, which demonstrate that the models possess excellent prediction powers(R2>0.74) The outliers suggested the involvement of non-transcellular passive diffusion,e.g.carrier mediated transport, paracellular route,ammonium groups,dose limited or dependent formation,the other way around,it is not the case with the octanol/water two-phase system which is the acting mechanism of oral drugs in the body. Therefore,the establishment of quantitative structure retention relationship for compounds with biopartitioning micellar chromatography contributes to the drug development program,improves the efficiency of research to predict oral absorption and development of new drugs, can then provide an elementary activity screening for massive quantities of drug candidates at early stage of the drug discovery process with high-throughput and at low consumption.The main effective components in Chinese herbal medicine extracts from radix et rhizoma rhei as rat intestinal absorptiontest in vivo perfusion fluid,using biopartitioning micellar chromatography (BMC) for chromatographic analysis of the absorption state of the active ingredients in the extracts in rat small intestine, capacity factor k as decision criteria, determination of the changes of effective component of the perfusate in rat small intestine,and considering the influence of the concentration change of absorption, according the literature and the result of our research,the results indicated that, the apparent intestinal absorption rate of the main effective components of chinese herbal medicine rhubarb in low, medium and high three kinds of concentrations in rat small intestine absorption mechanism is of passive diffusion mechanism,we think that applied BMC in the field of research traditional chinese medicine has certain feasibility and guiding significance.