title: Etoposide modulates the effects of oral morphine analgesia by targeting the intestinal P-glycoprotein.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Fujita-Hamabe
authors.forename: Mikako
authors.initials: M
authors.lastname: Nishida
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nawa
authors.forename: Takuro
authors.initials: T
authors.lastname: Kobori
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D020112:Rhodamine 123 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000972:Antineoplastic Agents, Phytogenic; D020112:Rhodamine 123; D005047:Etoposide; D009020:Morphine; D016572:Cyclosporine