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

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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.