Exposure of Cells to Hydrogen Peroxide Can Increase the Intracellular Accumulation of Drugs

One of the fastest growing areas of scientific research involves aspects of oxidative stress, either causes of or results from. Despite the enormous quantity of literature on the topic, surprisingly, the effects of oxidative stress on the pharmacokinetics of drugs have not been previously investigated. This is an extremely important concern, considering that the degree of oxidative stress that the human body experiences is known to be widely variable. Oxidative stress may be transiently increased, as is the case with some inflammatory episodes, or it may be chronically elevated, as is the case in some disease states, in aging, or with smokers. This report examines the influence of oxidative stress on the pharmacokinetics of model drugs utilizing cells in culture. Specifically, the effect of subtoxic, short-term exposure to hydrogen peroxide was investigated. Low micromolar, single doses of hydrogen peroxide were shown to cause dramatic increases in the apparent intracellular accumulation of model compounds with different physicochemical properties in different cell types. To examine the mechanistic basis for this, we evaluated possible hydrogen peroxide induced changes in cells including (1) intracellular pH, (2) membrane integrity, and (3) membrane fluidity (i.e., lateral membrane diffusion). We found no significant changes in pH or membrane integrity, but results were consistent with changes in hydrogen peroxide mediated reductions in lateral membrane diffusion, which we postulate facilitated the accumulation of the test substrates. Although studies presented here were all done in cell culture systems, we believe the findings could have substantial therapeutic relevance and warrant further investigations, which may provide reasons why drugs often have anomalous pharmacokinetic behavior and disproportionate dose−response relationships in certain patient populations. Keywords: Hydrogen peroxide; drug permeability; membrane fluidity; daunorubicin; Oregon Green