| Project/Area Number |
15590144
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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 | Osaka University of Pharmaceutical Sciences |
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Principal Investigator |
KAKEMI Masawo Osaka University of Pharmaceutical Sciences, Department of Pharmaceutics, Professor, 薬学部, 教授 (00019134)
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| Co-Investigator(Kenkyū-buntansha) |
IWANAGA Kazunori Osaka University of Pharmaceutical Sciences, Department of Pharmaceutics, Research Associate, 薬学部, 助手 (20257900)
MIYAZAKI Makoto Osaka University of Pharmaceutical Sciences, Department of Pharmaceutics, Research Associate, 薬学部, 助手 (10319593)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | tolbutamide / circadian rhythm / insulin / hypoglycemic effect / pharmacokinetics / pharmacodynamics / PK-PD Correlation / sulfonylureas / グルコーストランスポーター / スルホニルウレア / PK-PD解析 |
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| Research Abstract |
Pharmacokinetics (PK) and pharmacodynamics (PD) of hypoglycemic drugs may be influenced by dosage time, because plasma glucose level shows a remarkable circadian rhythm. The purpose of the present investigation was to evaluate the effect of circadian changes on the PK-PD relationship of tolbutamide (TB), a SU agent, in rats. Physiological level in plasma glucose showed a circadian rhythm with acrophase in the end of the light phase (ca.15:00 h). Plasma concentrations of free TB after i.v. bolus administration at 6:00 and 18:00 h were described using a two-compartment model, and no change of the PK parameters by the administration time was observed. The hypoglycemic effect after i.v. administration of TB at 18:00 h was larger than the 6:00 h dosage. The PK-PD model was constructed using link and E_<max> models with a circadian rhythm. However, the regression curves did not fit simultaneously the observed hypoglycemic effects at both dosage times well. For the insulin secretion by TB, plasma level and release from isolated pancreatic islets indicated that the spiked secretion of insulin enhanced at 18:00 h comparing with 6:00 h. The dosage of TB was therefore translated into the apparent dosage of insulin. To evaluate the relationship between the dosage of TB and the hypoglycemic effect, another model was then constructed using plasma level of insulin instead of TB. The model-estimated effect explained the observed data at both administration times simultaneously. These results suggest that a pharmacological change, which cannot be predicted from plasma drug concentration, might occur because of some biological circadian rhythms when SU agents are continued for a long time.
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