2007 Fiscal Year Final Research Report Summary
Establishment of drugs for probing in vivo activity of xenobiotic transporters in humans
| Project/Area Number |
18390046
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Medical pharmacy
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
KUSUHARA Hiroyuki The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor (00302612)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ONUKI Reko The University of Tokyo, Graduate School of Pharmaceutical Sciences, Assistant Professor (70361607)
MAEDA Kazuya The University of Tokyo, Graduate School of Pharmaceutical Sciences, Assistant Professor (00345258)
|
|---|
| Project Period (FY) |
2006 – 2007
|
| Keywords | transporter / drug dispostion / probe drug / tubular secretion / biliary excretion / intestine absorption / sinusoidal efflux |
|---|
| Research Abstract |
In the present study, to establish probe drugs which allows evaluation of in vivo transport activities of xenobiotic transporters in human, in vivo studies using gene knockout animal and in vitro transport studies using human kidney slices were carried out. The findings of the present study is as follows;
1) Mrp3 is involved in the sinusoidal efflux of anticancer drugs such as methotreate and SN-38 (an active form of irinotecan), and in the intestinal absorption of methotrexate.
2) Bcrp limits the brain penetration of phytoestrongens, dantrolene, prazosin and triamterene.
3) Human kidney slices allows evaluation of contribution of renal basolateral organic anion transporters, OAT1 and OAT3. In vitro study suggests that OAT1 mainly accounts for renal uptake of adefovir, and OAT3 for the uptake of olmesartan.
4) To examine the usefulness of probe drugs, PBPK model, in which transporter-mediated membrane transport process is taken into consideration, has been established for a model probe compound, pravastatin. Using in vitro-in vivo extrapolation coefficient, the predicted plasma concentrations following oral and intravenous administration fits the observed value.
In conclusion, methotrexate can be used for probing Mrp3 function, and adefovir for OAT1 and olmesartan for OAT3. As for Bcrp function at the blood brain barrier, phtytoestrogens and dantrolene can be used if they are labeled by 11C or 13N for PET analysis. These probe drugs will be used for investigating the mechanisms of drug-drug interaction, and interindividual difference in transport function due to genetic polymorphisms.
|
