title: Carvedilol-liposome interaction: evidence for strong association with the hydrophobic region of the lipid bilayers.
abstract: Carvedilol (Kredex, Coreg) is a multiple action antihypertensive drug that has been shown to protect cell membranes from lipid peroxidative damages. In this study the physical and structural effects of carvedilol on lipid bilayers are investigated by fluorescence techniques, differential scanning calorimetry and other physical methods. Carvedilol binds to liposomal membranes (9:1 DMPC:DMPG) strongly with an apparent binding constant on the order of 10(4) M-1 in PBS (pH 7.4). The characteristic changes in its intrinsic fluorescence properties when bound to liposomes suggest that this compound is situated in a non-polar environment. The Stern-Volmer and bimolecular quenching constants, determined using nitrate as the fluorescence quencher, for the free and bound carvedilol indicate that the carbazole moiety is at a depth of > 11 A in the lipid bilayer. Fluorescence anisotropy measurements show that, unlike the membrane probes DPH and TMA-DPH, carvedilol is relatively mobile, and does not have a rigidly-defined molecular orientation in the bilayers. Differential scanning calorimetry results indicate that carvedilol is an effective membrane "fluidizer' as it dose-dependently lowers the gel to liquid crystalline transition temperature and broadens the endothermic transition. Comparative studies of interactions of carbazole, 4-OH carbazole and carvedilol with the model liposomal membranes reveal a possible role of membrane-partitioning in their antioxidant efficacy. These findings are discussed in perspective with the membrane biophysical properties of different classes of therapeutic significant lipid antioxidants in mind.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. hy_cheng-1@sbphrd.com
authors.forename: H Y
authors.initials: HY
authors.lastname: Cheng
authors.forename: C S
authors.initials: CS
authors.lastname: Randall
authors.forename: W W
authors.initials: WW
authors.lastname: Holl
authors.forename: P P
authors.initials: PP
authors.lastname: Constantinides
authors.forename: T L
authors.initials: TL
authors.lastname: Yue
authors.forename: G Z
authors.initials: GZ
authors.lastname: Feuerstein
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D002227:Carbazoles / Q000737:chemistry*; D000077261:Carvedilol; D005453:Fluorescence; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D011412:Propanolamines / Q000737:chemistry*
chemical_list: D000959:Antihypertensive Agents; D002227:Carbazoles; D008051:Lipid Bilayers; D008081:Liposomes; D011412:Propanolamines; D000077261:Carvedilol