1. Inhibitory effect of cyclosporin A on p-glycoprotein function in peripheral nerves of mice treated with doxorubicin and vinblastine.
- Author
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Saito T, Zhang ZJ, Ohtsubo T, Noda I, Tokuriki M, Shibamori Y, Yamamoto T, and Saito H
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 drug effects, ATP Binding Cassette Transporter, Subfamily B, Member 1 physiology, ATP-Binding Cassette Transporters genetics, Animals, Antibiotics, Antineoplastic pharmacokinetics, Antibiotics, Antineoplastic therapeutic use, Antineoplastic Agents, Phytogenic pharmacokinetics, Antineoplastic Agents, Phytogenic therapeutic use, Cyclosporine pharmacokinetics, Doxorubicin therapeutic use, Drug Interactions, Immunosuppressive Agents pharmacokinetics, Immunosuppressive Agents pharmacology, Male, Mice, Neurotoxins pharmacology, Peripheral Nerves metabolism, Peripheral Nerves physiology, Tissue Distribution, Vinblastine therapeutic use, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Cyclosporine pharmacology, Doxorubicin pharmacokinetics, Neurotoxins pharmacokinetics, Peripheral Nerves drug effects, Vinblastine pharmacokinetics
- 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.
- Published
- 2004
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