| Project/Area Number |
16209005
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Medical pharmacy
|
|---|
| Research Institution | Kyoto University |
|---|
Principal Investigator |
INUI Ken-ichi Kyoto University, Faculty of Medicine, Professor, 医学研究科, 教授 (70034030)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KATSURA Toshiya Kyoto University, Graduate Shool of Medicine, Associate Professor, 医学研究科, 助教授 (10283615)
MASUDA Satohiro Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (90303825)
TERADA Tomohiro Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (10324641)
|
|---|
| Project Period (FY) |
2004 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥47,710,000 (Direct Cost: ¥36,700,000、Indirect Cost: ¥11,010,000)
Fiscal Year 2006: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2005: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2004: ¥29,640,000 (Direct Cost: ¥22,800,000、Indirect Cost: ¥6,840,000)
|
|---|
| Keywords | immunosuppressant / absorptive barrier / drug metabolizing enzyme / transporter / liver transplantation / calcineurin / tacrolimus / cyclosoorine / 肝臓移植治療 |
|---|
| Research Abstract |
1.Gene expression profile using human tissue specimens : The mRNA expression levels and genetic polymorphisms of MDR1,CYP3A4,CYP3A5,CYP3A7 and CYP3A43 were examined in the part of tissue specimens of native intestine (n=192) and graft liver (n=208). The mRNA expression level of MDR1 in the native small intestine at surgery was revealed to be a significant biomarker for adjustment of initial dosage of tacrolimus immediately after the living-donor liver transplantation. The data of single nucleotide polymorphism (SNP) of CYP3A5 in the graft liver was significantly associated with the dose escalation of tacrolimus by postoperative days.
2.Clarification of the pharmacokinetic- and pharmacodymanic-factors to associate the individual variation of immunosuppressant : The mRNA expression level of MDR1 at surgery, CYP3A5*3 SNP and graft-vs-recipients body weight ratio as well as the classical clinical test markers were found to be the statistical significant fixed effects by the population pharm
… More
acokinetic analyses. In addition, we found that the frequency of posttransplant acute cellular rejection was successfully reduced to around 30% by the initial dosage regimen tacrolimus based on the evaluation of intestinal expression level of MDR1 at surgery.
3.Clinical significance of gene expression information in the peripheral blood leukocyte : Focusing on the occurrence of acute cellular rejection after living-donor liver transplantation, the gene expression levels were examined with the total RNA fractions from the peripheral blood cells at postoperative days 3, 7 and 14. Using the pooled clinical samples over 500 points, the target therapeutic level of tacrolimus tended to be higher in the patients with high-expression level of MDR1 mRNA in blood cells rather than glucocorticoid receptor (GR/NR3C1).
These results suggested that various proteins in the tissues such as the MDR1 mRNA level in the native small intestine and peripheral leukocytes and CYP3A5 genotype in the graft liver and native intestine were pharmacokinetic and pharmacodynamic factors in living-donor liver transplant patients. By integrating these molecular factors, the strategy to prevent acute cellular rejection after liver transplantation must be established. However, the molecular mechanisms of interindividual variation of the response against tacrolimus should be clarified in future. Less
|
