The Research Of The Synthesis And The Targeting Of The Liver-target Prodrug

Prodrug is one of the most important way to target the active drug to the desired organs. The prodrugs can degrade and release the original drugs by the chemical reactions or the enzyme reactions in the body. We can diminish the adverse effect of the non-targeting organs by using the technology of the prodrug.Previous researches show that there are a great amount of bile acid transporter in the liver cells and the intestine apical cells including the hASBT and the NTCP. They can combine the bile acid especially and absorb the bile acid into the cells. From 1980s, there are a serial of researches conducted on bile acid to clear its character of especial combination. The result concluded that the using bile acid transporter can improve the bioavailability of the insoluble drugs; it can improve the drug concentration in liver at the same time diminishing the side effects of the other part of the human body. These researches also proved that the combining the drugs and the bile acid on the position C-24 will not weaken the combination of the bile acid transporter.Utilizing the deoxycholate as the carrier and the anti-HBV drug lamifudine as the model drug, we synthesis the prodrug by the chemical reactions.To research the stability and its metabolite velocity in vitro, we conduct the stability influence actor experiment and the degradation experiment in different solution and plasma and the tissue plasma. The result shows that the prodrug can hardly degrade in the 50% methanol and 50% ethanol; it will degrade a little amount in the manual gastric juice and the manual intestine juice. In the plasma and the liver tissue slurry, the prodrug has a distinct degradation: it will degrade 20.6%in the plasma and degrade 51.4% in the liver tissue slurry in 2 hours.We established the in-situ perfusion experiment models of the original drug and the prodrug to research the absorption difference between them. The result shows that the transport mechanism of the intestine absorption of the lamifudine is probably the passive diffusion, on the other hand, the absorption mechanism of the prodrug may be a process of active transportation.Using the mice as the animal models, we investigate the in vivo concentration of lamivudine and its prodrug by p.o. The result shows that the targeting effect of the prodrug is 5.96, the TE of the lamivudine is 1.32. The improvement of the targeting effect can prove the prodrug has a distinct character of liver targeting.The project prepared the prodrug of lamivudine for the first time in the world. At the same time we have studied the its stability and proved it could be used by p.o. We discussed the bioavailability and the liver targeting character by animal experiment. Compare to the original drug, we achieved the desired result.