| Project/Area Number |
63480474
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | The University of Tokyo |
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Principal Investigator |
IGA Tatsuji Fac. Medicine, Univ. of Tokyo, Professor, 医学部・附属病院, 教授 (60012663)
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| Co-Investigator(Kenkyū-buntansha) |
KURITA Masahiro Fac. Medicine, Univ. of Tokyo, Physician, 医学部・附属病院, 医局員
SUGIMOTO Tsuneaki Fac. Medicine, Univ. of Tokyo, Professor, 医学部・附属病院, 教授 (60019883)
SAWADA Yasufumi Fac. Medicine, Univ. of Tokyo, Associate Professor, 医学部・附属病院, 助教授 (80114502)
SUGIYAMA Yuichi Fac. Pharm. Sci., Univ. of Tokyo, Associate Professor, 薬学部・附属病院, 助教授 (80090471)
HANANO Manabu Fac. Pharm. Sci., Univ. of Tokyo, Professor, 薬学部・附属病院, 教授 (60012598)
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| Project Period (FY) |
1988 – 1990
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| Project Status |
Completed (Fiscal Year 1990)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1990: ¥100,000 (Direct Cost: ¥100,000)
Fiscal Year 1989: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1988: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Blood-brain barrier / cerebrospinal fluid / choroid plexus / renal failure / hepatic failure / 血液-脳関門 / 血液-脳脊髄液関門 / 脈絡叢 / 薬物速度論 / 薬物脳移行 / 腎障害ラット / イミブラミン / デシプラミン / DL-プロプラノロール |
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| Research Abstract |
The present studies were designed to examine the effect of serum from patients with renal or liver disease on the transport of propranolol into the rat brain. While the binding of propranolol to serum from cirrhotic patients was significantly decreased compared to normal serum, there was no change for the serum from patients with renal failure. In the carotid injection studies, the brain transport parameters such as the brain uptake index (BUI), the unidirectional extraction ratio (E), the bloodーbrain barrier permeability surface area product (PSapp), and PSapp corrected for the unbound fraction (PSu, app) in rats injected with serum from patients with renal failure were significantly reduced to approximately 40-53% of those in controls. No change in BUI, E, and PSapp was found in rats injected with serum from cirrhotic patients. However, the cirrhotic patients adopted in the present study had relatively mild liver disease (judging from the biochemical blood test), and we cannot refer
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to the more severe cirrhotic patients only from this study. Moreover, significant correlations were observed between the biochemical parameters (blood urea nitrogen, serum creatinine concentration) repesenting the degree of renal failure and the transport parameters (E, PSapp or PSu, app) of propranolol. As previously studied with the experimental acute renal failure rats, these results indicate that the decrease in the transport of propranolol into rat brain may also due to the presence of an inhibitory factor (s) in the serum from renal failure patients.
To elucidate the characteristics of promotion factor (s) in rat serum required for the protein-mediated transport of drugs into the brain, we examined the brain uptake of propranolol as a model drug using the in vivo BUI method in rats. The proteinーmediated transport was not observed in rats injected with the buffer solution containing either various concentrations of purified rat alpha1-acid glycoprotein (alpha1-AGP) or rat albumin. When the filtrate from rat serum was used as an injection vehicle to which a physiological concentration of purified rat serum proteins was added, the protein mediated transport of propranolol was observed in the rat brain. Moreover, the ability of protein-mediated transport of propranolol was reduced in rats injected with the dialyzed serum compared with the undialyzed serum. These results suggest that the dialyzable promotion factor in serum is required for the proteinーmediated transport of propranolol into the brain. Less
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