title: Permeability Coefficients of Lipophilic Compounds Estimated by Computer Simulations.
abstract: The ability of a drug to cross the intestine-blood barrier is a key quantity for drug design and employment and is normally quantified by the permeability coefficient P, often evaluated in the so-called Caco-2 assay. This assay is based on measuring the initial growth rate of the concentration of the drug beyond the cellular barrier but not its steady-state flux through the membrane. This might lead to confusion since, in the case of lipophilic drugs, the initial slope is strongly affected by the retention of the drug in the membrane. This effect is well known but seldom considered in the assay. Here, we exploit all-atoms molecular dynamics and bias exchange metadynamics to calculate the concentration of two lipophilic drugs across a model membrane as a function of time. This allows estimating both the steady-state flux and the initial slope of the concentration growth and comparing Caco-2 and steady-state estimates of P. We show that our computational procedure is able to reproduce the experimental values, although these may differ from the permeability coefficients by orders of magnitude. Our findings are generalized by a simplified one-dimensional model of the permeation process that may act as a roadmap to assess which measure of membrane permeability would be more appropriate and, consequently, whether retention corrections should be included in estimates based on Caco-2 assays.
authors.affiliation: SISSA, Scuola Internazionale Superiore di Studi Avanzati , via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Zhaleh
authors.initials: Z
authors.lastname: Ghaemi
authors.affiliation: Dipartimento Interateneo di Fisica "M. Merlin", University of Bari "Aldo Moro", TIRES & INFN , via Orabona 4, 70126 Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Alberga
authors.affiliation: Computational Biophysics, German Research School for Simulation Sciences , D-52425 Julich, Germany.|Institute for Advanced Simulation , Forschungszentrum Julich, D-52425 Julich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: SISSA, Scuola Internazionale Superiore di Studi Avanzati , via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laio
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale and INFN - Sez. di Bari , Viale Pinto, 71122 Foggia, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lattanzi
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000502:physiology*; D003521:Cyclopropanes; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D009570:Nitriles; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines; D013816:Thermodynamics
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D008051:Lipid Bilayers; D009570:Nitriles; D004364:Pharmaceutical Preparations; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; C098320:efavirenz