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

我们以往的研究表明，mdr1a P-糖蛋白(p-gp)定位于内耳的毛细血管内皮细胞，在血-内耳屏障中起着挤出泵的重要作用。本研究利用mdr1a p-gp基因敲除小鼠[mdr1a(-/-)小鼠]和野生型mdr1a(+/+)小鼠，研究了p-gp在内耳中的功能。药代动力学分析表明，mdr1a(-/-)小鼠对阿霉素和长春花碱等p-gp转运药物表现出超敏反应，与mdr1a(+/+)小鼠相比，这些药物在内耳的蓄积增加。但给予耳毒性药物顺铂后，p-gp的蓄积量并未增加，说明p-gp对药物的挤压具有选择性。使用听觉脑干反应的电生理学研究表明，仅在mdr1a(-/-)小鼠中，单独给予阿霉素或长春花碱后，阈值升高，I波和I波至V波的峰间潜伏期延长。此外，在mdr1a(+/+)小鼠中，与环孢菌素A联合给药抑制p-gp功能会增加阿霉素和长春花碱在内耳中的积聚。在环孢素A预处理后，仅用阿霉素或长春花碱处理的mdr1a(+/+)小鼠出现听力障碍。这些结果表明，mdr1a p-gp作为一种外排泵，能拮抗阿霉素和长春花碱等p-gp底物药物对野生型小鼠的耳毒性作用，并参与血-内耳屏障的新的作用机制。这项研究中观察到的药代动力学和功能变化表明，在没有适当的药理学和听力监测的情况下，在临床实践中应用这些组合时要谨慎。

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.