Pharmacokinetic and functional study on mdr1a p-glycoprotein function in blood-inner ear barrier

mdr1a p-糖蛋白在血-内耳屏障中的药代动力学和功能研究

• 批准号: 11671674
• 负责人: SAITO Takehisa
• 金额: $ 2.37万
• 依托单位: Fukui Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671674/
• 关键词: p-glycoprotein; mdr1a (-; -) mice; blood-inner ear barrier; doxorubicin; vinblastine; cyclosporin A; pharmacokinetics; auditory brainstem response

Our previous studies have shown that mdr1a p-glycoprotein (p-gp) was located in capillary endothelial cells of the inner ear and played an important role as an extrusion pump in blood-inner ear barrier. The present study investigated the p-gp function in the inner ear using mdr1a p-gp gene knock-out mice [mdr1a (-/-) mice] and wild-type mdr1a (+/+) mice. Pharmacokinetic analyses indicated that mdr1a (-/-) mice displayed hypersensitivity to p-gp transported drugs such as doxorubicin (adriamycin) and vinblastine, and increased accumulation of these drugs in the inner ear compared with that in mdr1a (+/+) mice. However, increased accumulation was not detected after administering with ototoxic drug cisplatin, indicating that p-gp had a selectivity for extruding drugs. Electrophysiological studies using auditory brainstem response showed elevated thresholds and prolongations of wave I and wave I to V interpeak latencies only in mdr1a (-/-) mice after administering with doxorubicin or vinblastine alone. Furthermore, inhibition of p-gp function by co-administration with cyclosporin A in mdr1a (+/+) mice resulted in increased accumulation of doxorubicin and vinblastine in the inner ear. After pretreatment with cyclosporin A, hearing impairment was detected in mdr1a (+/+) mice treated with doxorubicin or vinblastine alone. From these results, it was suggested that mdr1a p-gp, which acts as an efflux pump, prevented ototoxicity induced by p-gp substrate drugs such as doxorubicin and vinblastine in wild-type mice and contributed to a new functional mechanism in the blood-inner ear barrier. The pharmacokinetic and functional alterations observed in this study suggest caution in applying these combinations in clinical practice without appropriate pharmacological and hearing monitoring.

我们前期的研究表明，mdr1a p-糖蛋白（p-gp）定位于内耳毛细血管内皮细胞，在血-内耳屏障中起着重要的挤出泵作用。本研究使用mdr1a p-gp基因敲除小鼠[mdr1a（-/-）小鼠]和野生型mdr1a（+/+）小鼠研究了内耳中p-gp的功能。药代动力学分析表明，与mdr1a（+/+）小鼠相比，mdr1a（-/-）小鼠对p-gp转运药物如阿霉素（阿霉素）和长春碱表现出超敏反应，并增加了这些药物在内耳中的蓄积。然而，与耳毒性药物顺铂给药后，没有检测到增加的积累，表明p-gp具有选择性挤出药物。使用听觉脑干反应的电生理学研究显示，仅mdr1a（-/-）小鼠在单独给予多柔比星或长春碱后，阈值升高，I波和I至V波峰间潜伏期延长。此外，在mdr1a（+/+）小鼠中，通过与环孢菌素A联合给药抑制P-gp功能导致内耳中多柔比星和长春碱蓄积增加。在用环孢素A预处理后，在单独用阿霉素或长春碱处理的mdr1a（+/+）小鼠中检测到听力损伤。从这些结果可以看出，mdr1a p-gp作为外排泵，在野生型小鼠中防止了由p-gp底物药物如阿霉素和长春碱诱导的耳毒性，并在血液-内耳屏障中产生了新的功能机制。本研究中观察到的药代动力学和功能变化表明，在临床实践中应用这些组合时应谨慎，无需进行适当的药理学和听力监测。

项目成果

Zhi-Jian Zhang, et al.: "Disruption of mdr1a p-glycoprotein gene results in dysfunction of blood-inner ear barrier in mice"Brain Research. 852. 116-126 (2000)

张志坚等人：“mdr1a p-糖蛋白基因的破坏导致小鼠血液-内耳屏障功能障碍”大脑研究。

Takehisa Saito, Zhi-Jian Zhang, Toshio Ohtsubo, Ichiro Noda, Yoshiyuki Shibamori, Takehito Yamamoto, Hitoshi Saito: "Homozygous disruption of the mdr1a p-glycoprotein gene affects blood-nerve barrier in mice administered with neurotoxic drugs"Acta Otolary

Takehisa Saito、Zhi-Jian Zhu、Toshio Ohtsubo、Ichiro Noda、Yoshiyuki Shibamori、Takehito Yamamoto、Hitoshi Saito：“mdr1a p-糖蛋白基因的纯合破坏会影响服用神经毒性药物的小鼠的血神经屏障”Acta Otolary

Takehisa Saito, et al.: "Homozygous disruption of the mdr1a p-glycoprotein gene affects blood-nerve barrier in mice administered with neurotoxic drugs"Acta Otolaryngologica. (in press).

Takehisa Saito 等人：“mdr1a p-糖蛋白基因的纯合破坏会影响服用神经毒性药物的小鼠的血神经屏障”Acta Otolaryngologica。

Takehisa Saito, et al.: "Cyclosporin A inhibits the extrusion pump function of p-glycoprotein in the inner ear of mice treated with vinblastine and doxorubicin"Brain Research. (in press).

Takehisa Saito 等人：“环孢素 A 抑制长春碱和阿霉素治疗小鼠内耳中 p-糖蛋白的挤出泵功能”大脑研究。

Zhi-Jian Zhang, Takehisa Saito, Yuichi Kimura, Chizuru Sugimoto, Toshio Ohtsubo, Hitoshi Saito: "Disruption of mdr1a p-glycoprotein gene results in dysfunction of blood-inner ear barrier in mice"Brain Research. 852. 116-126 (2000)

张志坚、Takehisa Saito、Yuichi Kimura、Chizuru Sugimoto、Toshio Ohtsubo、Hitoshi Saito：“mdr1a p-糖蛋白基因的破坏导致小鼠血液-内耳屏障功能障碍”脑研究。