| Project/Area Number |
15590126
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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 | TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
HASHIMOTO Yukiya TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, PROFESSOR, 大学院・薬学研究科, 教授 (90228429)
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| Co-Investigator(Kenkyū-buntansha) |
AIBA Tetsuya TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, ASSOCIATE PROFESSOR, 大学院・薬学研究科, 助教授 (00231754)
TAGUCHI Masato TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY, GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, ASSISTANT PROFESSOR, 大学院・薬学研究科, 助手 (20324056)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | renal failure / bioavailability / hepatic metabolism / P450 / intestinal absorption / first-pass clearance / プロプラノロール / 薬物吸収 / CYP3A / CYP2D / 小腸 |
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| Research Abstract |
It has been reported that the bioavailability of propranolol was increased in patients with renal failure, and that the area under the concentration-time curve for orally administered propranolol in renal failure patients not on hemodialysis is 7-to 8-fold higher than that in healthy volunteers. To investigate the mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction, we studied the drug metabolism and pharmacokinetics using several experimental rat models with renal impairment.
We reported that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism. However, in bilateral ureter ligation (BUL)-induced renal failure, the absorption rate-dependent decrease in hepatic first-pass clearance of propranolol and metoprolol due to saturation kinetics is marginal, and the hepatic metabolic activity and extraction of the drugs is significantly decreased in BUL rats probably due to the reduced NADPH generation rate in the liver.
On the other hand, the hepatic and intestinal metabolic activities of P450 were evaluated in rats with surgery-and drug-induced renal dysfunction. Then we found (a) that only selected P450 metabolic activity in the liver is decreased in renal failure, (b) that extent of the decrease in hepatic metabolic activities of P450 is dependent on the etiology of renal failure, and (c) that alteration of CYP3A metabolic activity in the intestine is not always correlated with that in the liver. In addition, to further characterize the intestinal absorption of drugs, we established an assay system evaluating transcellular drug transport using Caco-2 cell monolayers.
These findings may provide new insight into the altered bioavailability of drugs during renal failure.
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