RhoA affects oral morphine analgesia depending on functional variation in intestinal P-glycoprotein induced by repeated etoposide treatment

In early palliative care, drug–drug interactions between opioids and anticancer agents may be caused by combined treatment with these drugs. We previously reported that repeated administration of oral etoposide (ETP), an anticancer drug that is a substrate of P-glycoprotein (P-gp), caused attenuation of the analgesic effect of oral morphine through up-regulation of intestinal P-gp. Recent studies have revealed that RhoA, a small G-protein, is involved in the regulation of P-gp expression and activity. Moreover, RhoA is known to be involved in various signaling pathways in response to anticancer drugs. Here, we examined the involvement of RhoA in the changes in ileal P-gp protein expression and activity induced by repeated orally administered ETP. Ileal P-gp and RhoA protein expression levels were analyzed using western blot analysis. The efflux activity of ileal P-gp was measured using the in situ closed loop method. The analgesic effect of oral morphine was determined with a tail-flick test. Repeated oral ETP significantly increased the activity of RhoA in association with up-regulation of P-gp protein expression and activity in the ileum. Interestingly, inhibition of RhoA activation by rosuvastatin prevented these effects. Furthermore, ETP-induced attenuation of the analgesic effect of oral morphine was also suppressed by rosuvastatin. RhoA activation induced by repeated oral ETP administration may be involved in the up-regulation of ileal P-gp protein expression and activity, leading to a decrease in the analgesic effect of oral morphine.