Inhibitory effect of cyclosporin A on p-glycoprotein function in peripheral nerves of mice treated with doxorubicin and vinblastine.
OBJECTIVE
To investigate the inhibitory effect of cyclosporin A on p-glycoprotein function in peripheral nerves (VIIth, VIIIth and sciatic nerves).


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.


CONCLUSIONS
When doxorubicin and vinblastine are co-administered with cyclosporin A, the patient should be carefully monitored because peripheral nerve disorders may be induced.
Saito
Takehisa
T
Department of Otolaryngology, Fukui Medical University, Yoshida-gun, Fukui, Japan. takehisa@fmsrsa.fukui-med.ac.jp
Zhang
Zhi-Jian
ZJ
Ohtsubo
Toshio
T
Noda
Ichiro
I
Tokuriki
Masaharu
M
Shibamori
Yoshiyuki
Y
Yamamoto
Takehito
T
Saito
Hitoshi
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000627:therapeutic use; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D009498:Neurotoxins / Q000493:pharmacokinetics* / Q000494:pharmacology; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014018:Tissue Distribution; D014747:Vinblastine / Q000493:pharmacokinetics* / Q000627:therapeutic use
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D007166:Immunosuppressive Agents; D009498:Neurotoxins; D014747:Vinblastine; D004317:Doxorubicin; D016572:Cyclosporine; C095122:multidrug resistance protein 3