Cyclosporin A inhibits the extrusion pump function of p-glycoprotein in the inner ear of mice treated with vinblastine and doxorubicin.
Cyclosporin A (CsA) inhibits the membrane transport protein p-glycoprotein (p-gp) and can enhance the accumulation of vinblastine (VBL) and doxorubicin (Dx) in the inner ear of mice. In mice pretreated with 200 mg/kg of CsA, there were significantly increased VBL and Dx concentrations detected in the inner ear tissue and other organs, with a small but significant increase in the brain. Furthermore, hearing thresholds measured by auditory brainstem responses were significantly elevated 3 weeks after VBL or Dx treatment in combination with CsA. However, the altered thresholds recovered to pretreatment levels 8 weeks after treatment. Pharmacokinetic and functional alterations observed in this study suggest caution in applying these combinations in clinical practice.
Saito
T
T
Department of Otolaryngology, Fukui Medical University, Matsuoka-cho, Yoshida-gun, 910-1193, Fukui, Japan. takehisa@fmsrsa.fukui-med.ac.jp
Zhang
Z J
ZJ
Tokuriki
M
M
Ohtsubo
T
T
Shibamori
Y
Y
Yamamoto
T
T
Saito
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000493:pharmacokinetics; D004347:Drug Interactions / Q000502:physiology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D007758:Ear, Inner / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014747:Vinblastine / Q000493:pharmacokinetics; D014781:Viscera / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D014747:Vinblastine; D004317:Doxorubicin; D016572:Cyclosporine