title: Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs.
abstract: The aim of this research was to gain a mechanistic understanding of ion-pair mediated membrane transport of low-permeability drugs. Quasi-equilibrium mass transport analyses were developed to describe the ion-pair mediated octanol-buffer partitioning and hydrophobic membrane permeation of the model basic drug phenformin. Three lipophilic counterions were employed: p-toluenesulfonic acid, 2-naphthalenesulfonic acid, and 1-hydroxy-2-naphthoic acid (HNAP). Association constants and intrinsic octanol-buffer partition coefficients (Log P(AB)) of the ion-pairs were obtained by fitting a transport model to double reciprocal plots of apparent octanol-buffer distribution coefficients versus counterion concentration. All three counterions enhanced the lipophilicity of phenformin, with HNAP providing the greatest increase in Log P(AB), 3.7 units over phenformin alone. HNAP also enhanced the apparent membrane permeability of phenformin, 27-fold in the PAMPA model, and 4.9-fold across Caco-2 cell monolayers. As predicted from a quasi-equilibrium analysis of ion-pair mediated membrane transport, an order of magnitude increase in phenformin flux was observed per log increase in counterion concentration, such that log-log plots of phenformin flux versus HNAP concentration gave linear relationships. These results provide increased understanding of the underlying mechanisms of ion-pair mediated membrane transport, emphasizing the potential of this approach to enable oral delivery of low-permeability drugs.
authors.affiliation: Center for Molecular Drug Targeting, Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Miller
authors.forename: Arik
authors.initials: A
authors.lastname: Dahan
authors.forename: Deepak
authors.initials: D
authors.lastname: Gupta
authors.forename: Sheeba
authors.initials: S
authors.lastname: Varghese
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D001557:Benzenesulfonates / Q000737:chemistry / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002021:Buffers; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions / Q000378:metabolism*; D008567:Membranes, Artificial; D015394:Molecular Structure; D009282:Naphthalenesulfonates / Q000737:chemistry / Q000378:metabolism; D009284:Naphthols / Q000737:chemistry / Q000378:metabolism; D000442:Octanols / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D010629:Phenformin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001557:Benzenesulfonates; D002021:Buffers; D007477:Ions; D008567:Membranes, Artificial; D009282:Naphthalenesulfonates; D009284:Naphthols; D000442:Octanols; D004364:Pharmaceutical Preparations; D010629:Phenformin; C534215:2-naphthalenesulfonic acid; C029501:4-toluenesulfonic acid; C050175:1-hydroxy-2-naphthoic acid