title: Inhibiting efflux with novel non-ionic surfactants: Rational design based on vitamin E TPGS.
abstract: Tocopheryl Polyethylene Glycol Succinate 1000 (TPGS 1000) can inhibit P-glycoprotein (P-gp); TPGS 1000 was not originally designed to inhibit an efflux pump. Recent work from our laboratories demonstrated that TPGS activity has a rational PEG chain length dependency. In other recent work, inhibition mechanism was investigated and appears to be specific to the ATPase providing P-gp energy. Based on these observations, we commenced rational surface-active design. The current work summarizes new materials tested in a validated Caco-2 cell monolayer model; rhodamine 123 (10microM) was used as the P-gp substrate. These results demonstrate that one may logically construct non-ionic surfactants with enhanced propensity to inhibit in vitro efflux. One new surfactant based inhibitor, Tocopheryl Polypropylene Glycol Succinate 1000 (TPPG 1000), approached cyclosporine (CsA) in its in vitro efflux inhibitory potency. Subsequently, TPPG 1000 was tested for its ability to enhance the bioavailability of raloxifene - an established P-gp substrate -in fasted male rats. Animals dosed with raloxifene and TPPG 1000 experienced an increase in raloxifene oral bioavailability versus a control group which received no inhibitor. These preliminary results demonstrate that one may prepare TPGS analogs that possess enhanced inhibitory potency in vitro and in vivo.
authors.affiliation: Eastman Chemical Company, Kingsport, TN 37662, USA. mwempe@eastman.com
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.forename: Charles
authors.initials: C
authors.lastname: Wright
authors.forename: James L
authors.initials: JL
authors.lastname: Little
authors.forename: Janet W
authors.initials: JW
authors.lastname: Lightner
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Large
authors.forename: George B
authors.initials: GB
authors.lastname: Caflisch
authors.forename: Charles M
authors.initials: CM
authors.lastname: Buchanan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rice
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Wacher
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ruble
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Edgar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013501:Surface-Active Agents / Q000737:chemistry* / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D013501:Surface-Active Agents; D014810:Vitamin E; D020112:Rhodamine 123; D011092:Polyethylene Glycols; D020849:Raloxifene Hydrochloride; C014225:tocophersolan