| Project/Area Number |
17590117
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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 | University of Toyama |
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Principal Investigator |
HASHIMOTO Yukiya UNIVERSITY OF TOYAMA, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, PROFESSOR, 大学院医学薬学研究部, 教授 (90228429)
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| Co-Investigator(Kenkyū-buntansha) |
NOZAWA Takashi UNIVERSITY OF TOYAMA, FACULTY OF MEDICINE, ASSOCIATE PROFESSOR, 大学院医学薬学研究部, 助教授 (00180737)
TAGUCHI Masato UNIVERSITY OF TOYAMA, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, ASSISTANT PROFESSOR, 大学院医学薬学研究部, 講師 (20324056)
HONDA Mutsuko UNIVERSITY OF TOYAMA, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, ASSISTANT PROFESSOR, 大学院医学薬学研究部, 助手 (60422630)
合葉 哲也 岡山大学, 大学院医歯薬学総合研究科, 助教授 (00231754)
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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: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | heart failure / β-blocker / pharmacokinetics / 人種差 / カルベジロール / ビソプロロール / メトプロロール / CYP2D6 |
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| Research Abstract |
Large clinical trials in Caucasians have shown a beneficial effect of p-blockers (carvedilol, metoprolol, and bisoprolol) on patients with chronic heart failure. On the other hand, low-dose carvedilol was approved for management of chronic heart failure in Japan. However, the mechanisms of difference between Caucasian and Japanese in the recommended dose of carvedilol and of large interindividual variability in the therapeutic outcomes of the drug were still unclear. The cytochrome P450 (CYP) 2D6 is involved in the hepatic metabolism of β-blockers, but a pronounced interethnic difference is present in the allele frequencies of CYP2D6. We previously reported that the oral clearance (CL/F) value of metoprolol was significantly decreased in Japanese patients with CYP2D6^*10. The purpose of this study was to clarify the mechanisms involved in the pharmacokinetic variability of carvedilol and bisoprolol, and to evaluate the pharmacodynamic variability of β-blockers under disease condition.
W
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e evaluated the effect of genetic polymorphisms of CYP (2D6, 2C9, 2C19, 3A5) and UDP-glucuronosyl-transferase (UGT) 2B7, and multidrug resistance 1 (MDR1) on the pharmacokinetics of carvedilol in healthy Japanese volunteers. The CL/F value of R- and S-carvedilol was significantly decreased in patients with CYP2D6^*10 allele, suggesting that CYP2D6^*10 is one of the major factors responsible for large pharmacokinetic variability of the drug. In contrast, the pharmacokinetic variability of bisoprolol was small in Japanese patients, provided that both body weight and renal function are taken into account for the prediction of CL/F of the drug. In addition, we elucidated the pharmacokinetics of bisoprolol in rats with experimental renal failure, and then evaluated the effect of renal failure on the pharmacodynamics of bisoprolol ; however, β-blocking action of the drug was not altered by renal failure. Our results may provide useful information about the use of β-blockers in management of heart failure. Less
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