| Project/Area Number |
17590121
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Kyoto University |
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Principal Investigator |
YANO Ikuko Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (50273446)
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| Co-Investigator(Kenkyū-buntansha) |
MASUDA Satohiro Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (90303825)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Tacrolimus / Cyclosporine / NONMEM / Calcineurin Activity / P-glycoprotein / CYP3A5 / Transplantation therapy / 母集団薬物動態解析 / 免疫抑制剤 / 生体肝移植 / カルシニューリン / MONMEM |
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| Research Abstract |
To compare the pharmacological characteristics of calcineurin inhibitors tacrolimus and cyclosporine, we measured the calcineurin activity in peripheral blood mononuclear cells as well as blood drug concentrations in living-donor liver transplant patients. Population Pharmacodynamic analysis using the nonlinear mixed-effects modeling program NONMEM showed that the calcineurin activity was almost completely inhibited over 700 ng/mL of cyclosporine which corresponded to the peak concentration. On the other hand, the calcineurin activity was partially inhibited over 20 ng/mL of tacrolimus which was the upper limit of therapeutic range, indicating that the pharmacological characteristics were different between tacrolimus and cyclosporine. Since the calcineurin inhibition by both drugs showed a large interindividual variability, the monitoring of calcineurin activity in addition to drug concentrations might be useful for individualized therapy. To clarify the factors affecting interindividual variability in tacrolimus pharmacokinetics, effects of P-glycoprotein (MDR1) and drug metabolizing enzymes (CYP3A4, CYP3A5) were analyzed by the population approach. As a result, mRNA levels of MDR1 in the intestine affected the oral clearance of tacrolimus immediately after the transplantation, while CYP3A5^*3 allele in the grafted liver influenced the recovery of oral clearance accompaning the postoperative days. Based on these results, the measurement of calcineurin activity in each patient and taking pharmacogenomic factors into consideration of pharmacokinetic changes will promote the precise individualized pharmacotherapy of tacrolimus.
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