Kinetic Analysis of the CNS Disposition of Drugs in the Renal and Hepatic Failure

肾、肝衰竭药物中枢神经系统分布的动力学分析

• 批准号: 63480474
• 负责人: IGA Tatsuji
• 金额: $ 2.05万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-63480474/
• 关键词: 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

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 … More 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

本研究旨在研究肾脏或肝脏疾病患者血清对普萘洛尔转运到大鼠脑中的影响。虽然与正常血清相比，普萘洛尔与糖尿病患者血清的结合率显著降低，但肾衰竭患者血清无变化。在颈动脉注射研究中，注射肾衰竭患者血清的大鼠的脑转运参数，如脑摄取指数（BUI）、单向提取率（E）、血脑屏障通透性表面积乘积（PSapp）和未结合分数校正的PSapp（PSu，app）显著降低至对照组的约40-53%。在注射了来自癫痫患者的血清的大鼠中，未发现BUI、E和PSapp的变化。然而，本研究中采用的肝病患者具有相对较轻的肝脏疾病（从生化血液检查判断），我们无法参考 ...更多信息 更严重的糖尿病患者的情况。此外，代表肾功能衰竭程度的生化指标（血尿素氮、血肌酐）与普萘洛尔转运参数（E、PSapp或PSu、app）之间也存在显著相关性。实验结果表明，在急性肾功能衰竭大鼠中，普萘洛尔脑转运的减少可能与肾功能衰竭患者血清中存在抑制因子有关，为了阐明大鼠血清中蛋白介导的药物脑转运所需的促进因子的特性，我们在大鼠中使用体内BUI方法检测了作为模型药物的普萘洛尔的脑摄取。在注射含有不同浓度纯化的大鼠α 1-酸性糖蛋白（α 1-AGP）或大鼠白蛋白的缓冲液的大鼠中，未观察到蛋白酶介导的转运。当从大鼠血清中的滤液被用作注射媒介物，其中加入生理浓度的纯化的大鼠血清蛋白质时，在大鼠脑中观察到普萘洛尔的蛋白质介导的转运。此外，与未透析血清相比，透析血清注射大鼠的普萘洛尔蛋白质介导转运能力降低。这些结果表明，血清中的可透析促进因子是必需的蛋白酶介导的普萘洛尔转运到脑中。少

项目成果

T-H. Lin, Y. Sugiyama, Y. Sawada, T. Iga and M. Hanano :"Dialyzable serum cofactors required for the protein-mediated transport of propranolol into rat brain." Biochem. Pharmacol.37 :. 2957-2961 (1988)

T-H。

A. Kurihara, H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga and M. Hanano :"Transport of digoxin into brain microvessels and choroid plexuses isolated from guinea pig." J. Pharm. Sci.77 :. 347-352 (1988)

A. Kurihara、H. Suzuki、Y. Sawada、Y. Sugiyama、T. Iga 和 M. Hanano：“将地高辛转运至从豚鼠分离的脑微血管和脉络丛中。”

H.Matsushita: "Facilitated transport cefodizime across the bloodーbrain barrier." J.Pharmacol.Exp.Ther.

H.Matsushita：“促进头孢地嗪穿过血脑屏障的转运。”

H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, M. Hanano and R. Spector :"Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system." J. Pharmacol. Exp. Ther.250,. 979-984 (1989)

H. Suzuki、Y. Sawada、Y. Sugiyama、T. Iga、M. Hanano 和 R. Spector：“亚胺培南（一种新型碳青霉烯类抗生素）在大鼠中枢神经系统中的转运。”

T. Nohjoh, H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga and M. Hanano :"Transport of cefodizime, a novel third generation cephalosporin antibiotic, in isolated rat choroid plexus." J. Pharmacol. Exp. Ther.250 :. 324-328 (1989)

T. Nohjoh、H. Suzuki、Y. Sawada、Y. Sugiyama、T. Iga 和 M. Hanano：“头孢地嗪（一种新型第三代头孢菌素抗生素）在离体大鼠脉络丛中的转运。”