2000 Fiscal Year Final Research Report Summary
Pharmacokinetic and functional study on mdr1a p-glycoprotein function in blood-inner ear barrier
| Project/Area Number |
11671674
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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 |
Otorhinolaryngology
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| Research Institution | Fukui Medical University |
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Principal Investigator |
SAITO Takehisa Fukui Medical University, Dept. of Otolaryngology, Associate Professor, 医学部, 助教授 (10139769)
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| Co-Investigator(Kenkyū-buntansha) |
SHIBAMORI Yoshiyuki Fukui Medical University Hospital, Dept. of Otolaryngology, Assistant, 医学部・附属病院, 助手 (10303380)
YAMADA Takechiyo Fukui Medical University, Dept. of Otolaryngology, Associate Professor, 医学部, 助手 (70283182)
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| Project Period (FY) |
1999 – 2000
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| Keywords | p-glycoprotein / mdr1a (- / -) mice / blood-inner ear barrier / doxorubicin / vinblastine / cyclosporin A / pharmacokinetics / auditory brainstem response |
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| Research Abstract |
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.
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