| Project/Area Number |
12557234
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Keio University |
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Principal Investigator |
TANIGAWARA Yusuke Keio University, School of Medicine, Professor, 医学部, 教授 (30179832)
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| Co-Investigator(Kenkyū-buntansha) |
MORITA Kunihiko Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (80327717)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2001: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2000: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | anticancer drug / pharmacokinetics / drug metabolizing enzyme / genotyping / CYP2D6 / CYP3A5 / S-1 / docetaxel / CYP3A5^*3 / TaqMan PCR法 / CYP3A4 / 薬物動態 / Population Pharmacokinetics / 遺伝子変異多型 / TaqManPCR法 / TS-1 / 5-FU / 薬物血中濃度モニタリング |
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| Research Abstract |
To develop the pharmacokinetic monitoring system in determining an optimal dosage of anticancer drugs, we have firstly established a rapid diagnosis method based upon the TaqMan PCR allelic discrimination assay for genetic polymorphisms of cytochrome P450 (GYP) 2D6^*10, CYP3A5^*3 and CYP3A5^*6 alleles, then we have investigated the factors causing the individual variability in pharmacokinetics of docetaxel and S-1.
Blood samples from 93 unrelated volunteers and 104 patients were collected for genotyping. The written informed consent was obtained from all subjects. The results of genotyping for CYP2D6 indicated that the frequency of CYP2D6^*1/^*10 (heterozygote) and CYP2D6^*10/^*10 (homozygote) were 43% and 23%, respectively. The results of genotyping for CYP3A5 indicated that the frequency of CYP3A5^*l/^*3 (heterozygote) and CYP3A5^*3/^*3 (homozygote) were 45% and 50%, respectively. The results indicated these are frequent variants in Japanese. No relationship was observed between docetaxel pharmacokinetics and CYP3A5 genotype in 13 NSCLC patients. The concentration of α 1-acid glycoprotein and the area under the plasma concentration-time curve (AUC) were more important determinants for the efficacy and toxicity of docetaxel.
The population pharmacokinetic and pharmacodynamic (PK/PD) analysis has been also performed for S-1, an oral anticancer agent. The plasma concentration of 5-fluorouracil (5-FU) was influenced by the plasma concentration of gimeracil, which is a DPD inhibitor. Renal insufficiency was found to be a risk factor for the toxicity by S-1, because delayed excretion of gimeracil caused higher exposure to 5-FU. Gastrointestinal toxicity (diarrhea) occurred more frequently in Western compared to Japanese patients, and in women compared to men. The present findings will be useful for the safe and optimal dosage of anticancer agents.
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