Effect of repeated oral treatment with etoposide on the expression of intestinal P-glycoprotein and oral morphine analgesia

Abstract

Currently, the World Health Organization recommends oral administration of opioid analgesics for patients with cancer to treat cancer-related pain from the initial stage of treatment. Furthermore, many anticancer drugs have been newly-developed and approved as oral form. Because of this trend, the chances of drug-drug interactions between anticancer drugs and opioid analgesics during absorption process from the intestine are likely to increase. To investigate these possible drug-drug interactions, we have focused on intestinal P-glycoprotein (P-gp) which regulates the absorption of various substrate drugs administered orally. Previously, we have found that repeated oral treatment with etoposide (ETP), an anticancer drug, attenuates analgesia of oral morphine, a substrate drug for P-gp, by increasing the expression and activity of intestinal P-gp. However, the mechanism by which ETP treatment increases the intestinal P-gp expression and decreases oral morphine analgesia remains unclear. RhoA, a small G-protein, and ROCK, an effector of RhoA, pathway has been attracted attention with regard to their involvement in the regulatory mechanism of the expression and activity of P-gp. Interestingly, this pathway is activated in response to various signaling induced by some anticancer drugs. Furthermore, it has been reported that ezrin/radixin/moesin (ERM) play a key role in the plasma membrane localization of P-gp, and that RhoA/ROCK pathway regulates the activation process of ERM. This review article introduces the result of our previous research as well as recent findings on the involvement of ERM via activation of RhoA/ROCK in the increased expression of intestinal P-gp and decreased oral morphine analgesia induced by repeated oral treatment with ETP.