title: Degradative transport of cationic amphiphilic drugs across phospholipid bilayers.
abstract: Drug molecules must cross multiple cell membrane barriers to reach their site of action. We present evidence that one of the largest classes of pharmaceutical drug molecules, the cationic amphiphilic drugs (CADs), does so via a catalytic reaction that degrades the phospholipid fabric of the membrane. We find that CADs partition rapidly to the polar-apolar region of the membrane. At physiological pH, the protonated groups on the CAD catalyse the acid hydrolysis of the ester linkage present in the phospholipid chains, producing a fatty acid and a single-chain lipid. The single-chain lipids rapidly destabilize the membrane, causing membranous fragments to separate and diffuse away from the host. These membrane fragments carry the drug molecules with them. The entire process, from drug adsorption to drug release within micelles, occurs on a time-scale of seconds, compatible with in vivo drug diffusion rates. Given the rate at which the reaction occurs, it is probable that this process is a significant mechanism for drug transport.
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Baciu
authors.forename: Sarra C
authors.initials: SC
authors.lastname: Sebai
authors.forename: Oscar
authors.initials: O
authors.lastname: Ces
authors.forename: Xavier
authors.initials: X
authors.lastname: Mulet
authors.forename: James A
authors.initials: JA
authors.lastname: Clarke
authors.forename: Gemma C
authors.initials: GC
authors.lastname: Shearman
authors.forename: Robert V
authors.initials: RV
authors.lastname: Law
authors.forename: Richard H
authors.initials: RH
authors.lastname: Templer
authors.forename: Christophe
authors.initials: C
authors.lastname: Plisson
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parker
authors.forename: Antony
authors.initials: A
authors.lastname: Gee
mesh_terms: D001693:Biological Transport, Active; D002412:Cations; D004058:Diffusion; D016503:Drug Delivery Systems; D066298:In Vitro Techniques; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D050866:Liquid Crystals; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D012542:Scattering, Radiation; D013501:Surface-Active Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D014965:X-Rays
chemical_list: D002412:Cations; D008051:Lipid Bilayers; D010743:Phospholipids; D013501:Surface-Active Agents