1995 Fiscal Year Final Research Report Summary
Pharmacokinetic Studies on Drug Excretion Mechanism Mediated by P-Glycoprotein
| Project/Area Number |
06672233
|
|---|
| Research Category |
Grant-in-Aid for General Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
医薬分子機能学
|
|---|
| Research Institution | KOBE UNIVERSITY |
|---|
Principal Investigator |
TANIGAWARA Yusuke Kobe University University Hospital Faculty of Medicine Associate Professor, 医学部・附属病院, 助教授 (30179832)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OKUMURA Katsuhiko Kobe University University Hospital Faculty of Medicine Professor, 医学部・附属病院, 教授 (60025707)
UEDA Kazumitsu Kyoto University Faculty of Agriculture Instructor, 農学部, 助手 (10151789)
|
|---|
| Project Period (FY) |
1994 – 1995
|
| Keywords | P-glycoprotein / MDR / Cyclosporin / PSC 833 / Reversal of resistance / Pharmacokinetics / Doxorubicin / Multidrug resistance |
|---|
| Research Abstract |
To investigate a mechanism of drug transport by P-glycoprotein, a quantitative analysis has been performed for structure-activity relationships. The drug transport by P-glycoprotein was measured by a transcellular transport system by introducing human MDRI cDNA into a porcine kidney epithelial cell line, LLC-PK_1.
The first study using a series of steroids showed that cortisol and dexamethasone, which are relatively lower lipophilic steroids, were well transported by P-glycoprotein, but that they did not possess an inhibitory effect on P-glycoprotein-mediated transport of drugs. On the other hand, steroids with higher lipophilicity showed a strong inhibitory effect, while they were not transported by P-glycoprotein. The transporting activity was not consistent with the inhibitory activity, suggesting a multiplicity of transporting mechanism of P-glycoprotein.
The next study investigated the inhibitory effect of cyclosporin analogs on P-glycoprotein-mediated transcellular transport of sev
… More
eral anticancer agents. The lipophilic cyclosporin analogs inhibited P-glycoprotein-mediated transport of daunorubicin, doxorubicin and vinblastine. The rank order of the inhibitory activity was SDZ PSC 833 > cyclosporin D,dihydrocyclosporin D > cyclosporin A > cyclosporin C,dihydrocyclosporin C.The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect depended on the concentration of cyclosporins. The inhibitory effect on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity.
The phase I study of the combination of the most potent agent, SDZ PSC 833 and doxorubicin was conducted to determine the maximum tolerated dose of these two agents as well as to investigate the drug interaction in pharmacokinetics. The doxorubicin clearance was decreased with increased blood concentration of SDZ PSC 833, indicating that the inhibition of P-glycoprotein function could change drug distribution and elimination. These findings are useful for developing a new chemotherapy to target P-glycoprotein. Less
|
