Drug metabolism and transport under hypoxia

Tumour progression is characterized by a rapid cell growth accompanied by changes in the microenvironment, largely due to hypoxia. The angiogenic switch involves changes in the expression of genes that play key roles in tumour progression, invasion, metastasis and therapeutic response, contributing to tumour aggressiveness. The effect of hypoxia on the cellular concentrations of drug metabolizing enzymes and transporters is much less understood. A brief summary of the signaling mechanisms triggered by hypoxia is presented, followed by a review of the known effects of hypoxia on drug metabolism and transport. Most of the studies available have focused on Cytochromes P450 and ATP-binding cassette transporters, while influx transporters of the SLC family have been less investigated. Given its potential to contribute both to the understanding of the pathogenesis of disease and to the optimization of therapeutics, it is rather surprising that this area of research is still underdeveloped. An increasing number of studies focusing on this subject are bound to provide key information for drug development and optimization of therapeutics.