OXALIPLATIN AND OTOTOXICITY

Why the Difference in Ototoxicity Between Cisplatin and Oxaliplatin?

December 30, 2008 — Ototoxicity is a well-recognized adverse effect of cisplatin, resulting in hearing loss and tinnitus. It is often dose-limiting and can hamper optimal cisplatin-based chemotherapy. The related third-generation platinum compound, oxaliplatin (Eloxatin, Sanofi-Aventis) appears to be free of this adverse effect, and new studies have shed light as to why there is such a difference between the 2 drugs.

"Pharmacokinetic differences between cisplatin and oxaliplatin may be sufficient to explain their different ototoxic profiles," say researchers from the Karolinska Institute, in Sweden. In the January 7 issue of the Journal of the National Cancer Institute, they report studies showing differences in the way the 2 drugs are transported from the blood to the extracellular compartments of the cochlea in the inner ear.

The inner ear is protected by a blood-labyrinth barrier, in a manner analogous to the way that the central nervous system is protected by the blood-brain barrier, the researchers explain. This barrier consists mainly of endothelial cells sealed by tight junctions, and in the inner ear, it is most likely the major barrier for pharmacological substances in reaching the sensory epithelium of the hearing and balance organs.

The researchers, headed by Victoria Hellberg, MD, conducted a series of experiments in guinea pigs, which involved — among other procedures — obtaining samples from the scala tympani perilymph from the cochlea, a task that "is highly demanding methodologically," they comment. Using these samples, they showed that drug concentrations and also the total concentration of platinum in the perilymph section of the blood-labyrinth barrier were lower after oxaliplatin than after cisplatin administration, even though both drugs were administered at equimolar doses. "Limited cochlear uptake of oxaliplatin is a major explanation for the lower ototoxicity of oxaliplatin than cisplatin," the researchers conclude.

One limitation of their study, they say, is that it was conducted in guinea pigs. "It should not be taken for granted that human subjects have the same cochlear pharmacokinetics," they write. However, they point out that "for technical and ethical reasons, it is impossible to repeat our experiments in human subjects. We do believe, though, that the major aspects of our conclusions are valid for humans."