Open AccessEtoposide modulates the effects of oral morphine analgesia by targeting the intestinal P‐glycoprotein
Author(s) -
FujitaHamabe Wakako,
Nishida Mikako,
Nawa Ayaka,
Kobori Takuro,
Nakamoto Kazuo,
Kishioka Shiroh,
Tokuyama Shogo
Publication year - 2012
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/j.2042-7158.2011.01426.x
Subject(s) - morphine , pharmacology , etoposide , p glycoprotein , analgesic , efflux , medicine , opioid , drug interaction , rhodamine 123 , drug , chemotherapy , chemistry , multiple drug resistance , receptor , biochemistry , antibiotics
Objectives Opioids and anticancer compounds such as etoposide (ETP) are substrates of P‐glycoprotein (P‐gp), an ATP‐dependent efflux pump. Chemotherapy compounds may impact on the analgesic effect of opioids such as morphine when the two drugs are co‐administered. In this study, we used a mouse model to determine if there is a pharmacological interaction between ETP and morphine, focusing on the involvement of intestinal P‐gp. Methods P‐gp drug efflux activity was measured by an in‐situ closed loop method with Rhodamine 123, a P‐gp substrate. The analgesic effect of morphine was determined by the tail‐flick test. Intestinal P‐gp expression levels were determined by Western blot. Key findings ETP and morphine significantly decreased the intestinal Rhodamine 123 efflux activity of P‐gp. Oral morphine analgesia was significantly enhanced when co‐administered with ETP. However, repeated pretreatment (7 days) with oral ETP significantly decreased the oral morphine‐induced analgesia, in a cyclosporine A (a P‐gp inhibitor) reversible manner. Furthermore, repeated ETP significantly up‐regulated intestinal P‐gp expression. Conclusions It may be important to consider aspects of therapeutic design such as the administration route or scheduling of drugs in patients receiving concurrent chemotherapy and opioid therapy to avoid pharmacokinetic interactions between the two agents.