title: Genomic evaluation during permeability of indomethacin and its solid dispersion.
abstract: Drug resistance was first identified in cancer cells that express proteins known as multidrug resistance proteins that extrude the therapeutic agents out of the cells resulting in alteration of pharmacokinetics, tissue distribution, and pharmacodynamics of drugs. To this end studies were carried out to investigate the role of pharmacological inhibitors and pharmaceutical excipients with a primary focus on P-glycoprotein (P-gp). The aim of this study was to investigate holistic changes in transporter gene expression during permeability upon formulation of indomethacin as solid dispersion. Initial characterization studies of solid dispersion of indomethacin showed that the drug was dispersed within the carrier in amorphous form. Analysis of permeability data across Caco-2 monolayers revealed that drug absorption increased by 4-fold when reformulated as solid dispersion. The last phase of the work involved investigation of gene expression changes of transporter genes during permeability. The results showed that there were significant differences in the expression of both ATP-binding cassette (ABC) transporter genes as well as solute carrier transporter (SLC) genes suggesting that the inclusion of polyethylene glycol as well as changes in molecular form of drug from crystalline to amorphous have a significant bearing on the expression of transporter network genes resulting in differences in drug permeability.
authors.affiliation: Aston Pharmacy School, Aston University, Birmingham, UK.
authors.forename: Sheraz
authors.initials: S
authors.lastname: Khan
authors.forename: Amr
authors.initials: A
authors.lastname: Elshaer
authors.forename: Ayesha S
authors.initials: AS
authors.lastname: Rahman
authors.forename: Peter
authors.initials: P
authors.lastname: Hanson
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Perrie
authors.forename: Afzal R
authors.initials: AR
authors.lastname: Mohammed
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000042:Absorption; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002463:Cell Membrane Permeability / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D015870:Gene Expression; D006801:Humans; D007213:Indomethacin / Q000737:chemistry / Q000493:pharmacokinetics*; D046228:Microarray Analysis; D008855:Microscopy, Electron, Scanning; D025341:Principal Component Analysis; D012995:Solubility; D013053:Spectrophotometry; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D007213:Indomethacin