Preliminary Study On The Pharmacokinetics, Tissue Distribution And Brain Injury Protection Of Leonurine O/O Microemulsion

Leonurine is the main plant alkaloid present in Chinese motherwort（also calledYi-Mu-Cao in the traditional Chinese medicine）.Modern pharmacological studieshave shown that Leonurine not only have uterotonic action, antiplatelet aggregationactivities, lowered blood viscosity and promoted blood circulation, but also have asignificant role in cardiovascular and cerebrovascular diseases, which is expected tobecome a promising drug candidates for cardiovascular and cerebrovascular diseases.However, Leonurine is insoluble in water, poor oral absorption, fast elimination and alow concentration in vivo. The disadvantages severely limit its formulation researchand clinical applications. Microemulsion, as a new drug delivery system, has beenshown to be able to increase drugs solubility, promote the absorption of drugs andimprove the bioavailability. Currently, Leonurine was made into O/O microemulsionloading with Leonurine by the best preparation method and technology. We comparedthe differences of pharmacokinetic effects and tissue distribution for O/Omicroemulsion formulation for Leonurine with water suspension formulation. Toexplore the preliminary pharmacodynamic of Leonurine on brain injury protection, byobserving the effect of Leonurine on the expression of NF-κB and TNF-α inhippocampal region of the rats with Alzheimer’s disease model.In this thesis, an HPLC method was developed and validated to measure theLeonurine concentration in plasma, heart, liver, spleen, lung, kidney, brain. Themethod had a linear range from0.010-15.000μg·ml^-1. The intra-day and inter-dayRSD were less than10%. The method has been applied for related pharmacokineticstudy and tissue distribution study of Leonurine. The pharmacokinetics of low andhigh concentrations of Leonurine microemulsion were studied in rats, the suspensionof Leonurine as the control group. The results showed that the microemulsion dose inrats was in0.15-0.3mg·g^-1, the peak time was about2hour. As the dose increased, theabsorption peak （Cmax） and AUC（0-∞）were also a corresponding increase. Relative bioavailability was629.547%, and extended the average residence time in vivo byabout8.132hour. Microemulsion of Leonurine showed an obvious sustained releaseeffect than the suspension.From the study of tissue distribution, microemulsion of Leonurine was3.626-26.265times more than suspension of Leonurine in mice, relative targeting efficiency of heart,liver, spleen, lung, kidney and brain were4.948%,-33.802%,-25.013%,34.173%,-1.199%,379.435%. The drug targeting index （DTI） of heart, lung and brain were1.044,1.335,4.769, DTI>1showed a strong targeting. The results showed that themicroemulsion of Leonurine had a strong targeting on brain.By immuonhistochemical technique, Leonurine could decrease the positive expressionof NF-κB and TNF-α, compared with the model group, the difference was statisticallysignificant （p<0.05）. the results showed Leonurine could inhibit the activation ofNF-κB, thereby the expression of a series of inflammatory factors （such as TNF-α）were blocked by NF-κB, so Leonurine could improve the rat brain injury caused byAlzheimer’s disease, and played a protective effect.