| Research Abstract |
One of the most important factors to determine the oral bioavailability is the small intestinal absorption. Since the substrate specificity of CYP3A and MDR1 P-glycoprotein resembles each other, the oral absorption of many drugs is prohibited by the synergistic role of these proteins. In order to determine the relative role of CYP enzymes and P-glycoprotein, an effort was made to determine the selective inhibitors. It was demonstrated that L754,394 and PSC 833 are selective for CYP3A4 and MDR1 P-glycoprotein, respectively. The contribution of these proteins may be determined by using human small intestine in vivo.
In addition, it is possible that many anionic drugs can be eliminated by efflux transporters located in the small intestine. We have particularly focused on the function of multidrug resistance associated protein (MRP) family proteins. MRP2 is expressed on the apical membrane. By comparing the intestinal excretion between normal and MRP2-deficient rats, it was demonstrated that MRP2 prohibits the absorption of anionic drugs. In contrast, MRP3 is located on the basolateral membrane of enterocytes. It was found that MRP3 accepts glucuronide conjugates, sulfated bile acids, non-conjugated organic anions, and monovalent bile salts. Furthermore, by using the basolateral membrane from the small intestine, it was revealed that un-identified MRP family protein (s) is responsible for the ATP-dependent transport of glucuronide conjugates. By regulating the function of these efflux transporters, it is possible to enhance the oral bioavailability.
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