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Objective: To investigate the inhibitory effect of cyclosporin A on p-glycoprotein function in peripheral nerves (VIIth, VIIIth and sciatic nerves)., Material and Methods: Male mdr1a(-/-) and mdr1a(+/+) FVB mice were used. Doxorubicin (30 mg/kg) was administered intravenously with or without i.p. administration of cyclosporin A (200 mg/kg). Vinblastine (5 mg/kg) was also administered intravenously with or without i.p. administration of cyclosporin A (200 mg/kg)., Results: Tissue concentrations of doxorubicin and vinblastine in peripheral nerves of the mdr1a(+/+) mice pretreated with 200 mg/kg cyclosporin A were significantly higher than those in the mdr1a(+/+) mice administered doxorubicin or vinblastine alone, suggesting that cyclosporin A inhibited the efflux pump function of p-glycoprotein in the peripheral nerves. In the mdr1a(-/-) mice, tissue concentrations of doxorubicin and vinblastine in peripheral nerves were also significantly higher than those in the mdr1a(+/+) mice administered doxorubicin or vinblastine alone. Based on these results, it is suggested that p-glycoprotein plays an important role in blood-nerve barrier function by preventing side-effects induced by neurotoxic drugs., Conclusion: When doxorubicin and vinblastine are co-administered with cyclosporin A, the patient should be carefully monitored because peripheral nerve disorders may be induced.

Although doxorubicin [adriamycin (ADM)] ototoxicity has not been detected to date, it has been reported that neurotoxicity in the central nervous system was induced by chemotherapy with ADM in patients receiving chronic cyclosporin A (CsA) treatment. ADM ototoxicity may be induced by combination therapy with CsA because extrusion of ADM from the inner ear by p-glycoprotein (p-gp), which acts as an extrusion pump and is expressed on the surface of endothelial cells of capillary blood vessels, might be inhibited by CsA, resulting in significant accumulation of ADM in the inner ear. ADM (10 mg kg) was administered to FVB mice either with or without CsA (200 mg kg). Auditory brainstem responses (ABRs) were recorded before and after treatment. ABR changes were not observed in mice treated with either ADM or CsA alone. Threshold elevation, elongation of wave I-V latencies and interpeak latencies of waves I-II, I-III, I-IV and I-V were detected in mice treated with ADM in combination with CsA. These changes reached their peak values 3 weeks after treatment, and then recovered to pre-treatment levels. In normal mice, ADM is extruded by p-gp from the inner ear and auditory pathway, thus preventing hearing disorder. However, ADM ototoxicity was induced by combination therapy with CsA, indicating that CsA has an inhibitory action on p-gp function in the auditory pathway, including the inner ear. After organ transplantation, therefore, clinical administration of ADM in combination with CsA should be performed with caution. [ABSTRACT FROM AUTHOR]

We investigated the expression and function of mdr1a p-glycoprotein in peripheral nerves, including the VIIth and VIIIth nerves, using mdr1a p-glycoprotein gene knockout mice [mdr1a(-/-) mice] and wild-type mdr1a(+/+) mice. P-glycoprotein expression in capillary endothelial cells of the peripheral nerve tissues was detected by immunohistochemical and RT-PCR analyses in mdr1a(+/+) mice but not in mdr1a(-/-) mice. Pharmacokinetic analyses indicated that, compared to mdr1a(+/+) mice, mdr1a(-/-) mice showed a significantly higher accumulation of p-glycoprotein substrate drugs such as vinblastine and doxorubicin, which are neurotoxic. Tissue concentrations of vinblastine and doxorubicin were lower in the order of the brain, peripheral nerves and most other organs. However, increased accumulation was not detected after administering another neurotoxic drug, cisplatin, indicating that p-glycoprotein is selective at extruding drugs. These data indicate that mdr1a p-glycoprotein, which acts as an efflux pump, might play an important role in the blood-nerve barrier to prevent side effects induced by neurotoxic p-glycoprotein substrate drugs. The participation of p-glycoprotein in the blood-nerve barrier is considered to represent a new functional mechanism of this barrier. [ABSTRACT FROM AUTHOR]