Expression of drug metabolizing enzymes and transporters in the cochlea: Implications for drug delivery and ototoxicity

摘要

Inner ear drug delivery is a major area of research and development, but relatively little is known about basic drug metabolism in the cochlea. Additionally, the use of potentially ototoxic drugs such as NSAIDs, chemotherapeutics and aminoglycosides is common, but little is known about the role of metabolism in ototoxicity of those drugs. To address those issues, we compared expression of major Cytochromes P450 (Cyps), UDP-glucuronosyl-transferases (Ugts), sulfotransferases (Sults), and drug transporters between cochleae and liver, an organ with high expression, in mice using qPCR and enzyme kinetics. Together, the tested drug-metabolizing enzymes (DMEs) and transporters account for metabolism of approximately 70-80% of all medically important drugs in the body. Expression of most Cyps was low in the cochlea compared to liver, but three displayed similar expression levels to the liver, and one (Cyp2c65) had significantly higher levels of expression in the cochlea (1.9 +/- 0.06 fold vs. liver). Enzyme kinetics revealed undetectable levels of p450 activity in the cochlea, especially as compared to the liver. Similar results were obtained for expression of Ugts and Sults. Interestingly, expression of most transporters was also low, with one major exception: Mdr1/P-glycoprotein (P-gp), which is generally thought to be highly expressed in liver and poorly expressed in most of the nervous system, was 3-fold greater in cochlea. Importantly, P-gp is known to protect other tissues from toxicity of cancer drugs by acting as an efflux pump. Our data demonstrate overall low levels of expression of DMEs and transporters in the cochlea, and identify a few that may be important to consider when designing and testing drugs for local delivery to the inner ear. (C) 2019 Elsevier B.V. All rights reserved.