title: Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations.
abstract: BACKGROUND
  Malaria is a major health concern and affects over 300million people a year. Accordingly, there is an urgent need for new efficacious anti-malarial drugs. A major challenge in developing new anti-malarial drugs is to design active molecules that have preferable drug-like characteristics. These "drug-like" characteristics include physiochemical properties that affect drug absorption, distribution, metabolism, and excretion (ADME). Compounds with poor ADME profiles will likely fail in vivo due to poor pharmacokinetics and/or other drug delivery related issues. There have been numerous assays developed in order to pre-screen compounds that would likely fail in further development due to poor absorption properties including PAMPA, Caco-2, and MDCK permeability assays.
  
  
  METHODS
  The use of cell-based permeability assays such as Caco-2 and MDCK serve as surrogate indicators of drug absorption and transport, with the two approaches often used interchangeably. We sought to evaluate both approaches in support of anti-malarial drug development. Accordingly, a comparison of both assays was conducted utilizing apparent permeability coefficient (Papp) values determined from liquid chromatography/tandem mass spectrometry (LC-MS) analyses.
  
  
  RESULTS
  Both Caco-2 and MDCK permeability assays produced similar Papp results for potential anti-malarial compounds with low and medium permeability. Differences were observed for compounds with high permeability and compounds that were P-gp substrates. Additionally, the utility of MDCK-MDR1 permeability measurements was demonstrated in probing the role of P-glycoprotein transport in Primaquine-Chloroquine drug-drug interactions in comparison with in vivo pharmacokinetic changes.
  
  
  CONCLUSIONS
  This study provides an in-depth comparison of the Caco-2 and MDCK-MDR1 cell based permeability assays and illustrates the utility of cell-based permeability assays in anti-malarial drug screening/development in regard to understanding transporter mediated changes in drug absorption/distribution.
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Xiannu
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Thu-Lan
authors.initials: TL
authors.lastname: Luong
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Necole
authors.initials: N
authors.lastname: Reese
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Gaona
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Collazo-Velez
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Chau
authors.initials: C
authors.lastname: Vuong
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Brittney
authors.initials: B
authors.lastname: Potter
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Sousa
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Raul
authors.initials: R
authors.lastname: Olmeda
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Greg
authors.initials: G
authors.lastname: Reichard
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States. Electronic address: sean.r.marcsisin.mil@mail.mil.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Marcsisin
authors.affiliation: Department of Drug Development, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Pybus
mesh_terms: D065567:Absorption, Physiological / Q000187:drug effects; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004285:Dogs; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010539:Permeability / Q000187:drug effects; D053719:Tandem Mass Spectrometry
chemical_list: D000962:Antimalarials
keywords: Anti-malarial drug development; Caco-2; MDCK; MDCK-MDR1; Permeability; Primaquine–Chloroquine interaction