Blood Flow-independent Accumulation of Cisplatin in the Guinea Pig Cochlea

Abstract

Considerable interindividual variability in the ototoxic effect of cisplatin has become the unpredictable dose-limiting factor in its use as curative as well as palliative therapy. The drug accumulates in highly vascular areas in the cochlea, causing dose-related hair cell loss. The purpose of this study was to assess blood flow-dependent aspects of cisplatin absorption in the cochlea in order to better understand factors that may influence cisplatin-induced ototoxicity. The effect of reduced cochlear blood flow on the ototoxic action of cisplatin was studied in guinea pigs. Before cisplatin administration the cochlear vasculature in each animal was unilaterally pre-constricted, by the application of 2% epinephrine to the round window. A 20-30% reduction in cochlear blood flow, assessed by laser Doppler flowmetry, was maintained before and after intravenous infusion of 0.1% cisplatin. Cisplatin infusion affected cochlear blood flow but not vessel conductivity. The cochlear blood flow decrease, maintained by local epinephrine application to the round window during cisplatin infusion, did not alter the cisplatin-induced hearing loss. In addition, the concentration of free cisplatin in scala tympani perilymph did not differ between epinephrine-treated and non-treated ears. Our results indicate that cisplatin transport into the cochlea is not an energy-dependent process in the lateral wall vasculature.