Inhibitory effect of cyclosporin A on p-Glycoprotein function in peripheral nerves of mice treated with doxorubicin and vinblastine

Abstract

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.

• blood–nerve barrier
• drug extrusion pump
• mdr1a(+/+) mice
• mdr1a(−/−) mice
• neurotoxic drugs
• pharmacokinetics
• sciatic nerve
• VIIth nerve
• VIIIth nerve

Saito T, Zhang Z-J, Ohtsubo T, Noda I, Tokuriki M, Shibamori Y, Yamamoto T, Saito H. Inhibitory effectof of cyclosporin A on p-glycoproteing function in peripheral nerves of mice treated with doxorubicin and vinblastine. Acta Otolaryngol 2004; 124: 313–317.

Saito T, Zhang Z-J, Ohtsubo T, Noda I, Tokuriki M, Shibamori Y, Yamamoto T, Saito H. Inhibitory effectof of cyclosporin A on p-glycoproteing function in peripheral nerves of mice treated with doxorubicin and vinblastine. Acta Otolaryngol 2004; 124: 313–317.