pgp - publications

Predict more pgp - ligand interactions now!


1. J Pharm Pharmacol. 2012 Apr;64(4):496-504. doi: 10.1111/j.2042-7158.2011.01426.x.
Epub 2011 Dec 29.

Etoposide modulates the effects of oral morphine analgesia by targeting the
intestinal P-glycoprotein.

Fujita-Hamabe W, Nishida M, Nawa A, Kobori T, Nakamoto K, Kishioka S, Tokuyama S.

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin
University, Kobe Department of Pharmacology, Wakayama Medical University,
Wakayama, Japan.

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.

© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

PMID: 22420656 [PubMed - in process]