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.