title: Opioids and efflux transporters. Part 1: P-glycoprotein substrate activity of N-substituted analogs of meperidine.
abstract: P-Glycoprotein (P-gp) is an efflux transporter which is up-regulated at the blood-brain barrier in both morphine- and oxycodone-tolerant rats. Numerous studies have shown that many clinically employed opioid analgesics are substrates for P-gp, suggesting that up-regulation of P-gp may contribute to the development of central tolerance to opioids. The studies herein focus on the development of SAR for P-gp substrate activity in the meperidine series of compounds, and show that a meperidine analog of greater potency, N-phenylbutyl-N-normeperidine, has low activity as a P-gp substrate and has the potential to be utilized as a tool to study the contribution of P-gp to the development of central tolerance to opioids.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, 20 Penn Street, Room 637, Baltimore, MD 21201, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mercer
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Hassan
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cunningham
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004361:Drug Tolerance; D008614:Meperidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000701:Analgesics, Opioid; D008614:Meperidine