Transporter-­driven Vectorial Transport of Cationic, Anionic, and Zwitterionic Drugs in the Intestine

Date: May 07 2014
Presenter(s): Dr. Dhiren R. Thakker, Ph.D.

Webinar presented on May 7th, 2014 by Dhiren R. Thakker, Ph.D., Ferguson Distinguished Professor and Associate Dean, Entrepreneurial Development and Global Engagement UNC Eshelman School of Pharmacy The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Summary of the presentation

Intestinal epithelium is the first line of defense for all ingested food products, drugs, and xenobiotics. Accordingly, its physical and biochemical architecture is highly specialized to perform the dual function of assisting absorption of nutrients while keeping foreign compounds from accessing the systemic circulation. Transporters play a major role in both assisting as well as attenuating absorption of many drugs, particularly those that are charged at physiologic pH values. For hydrophilic and charged compounds that cannot cross cell membrane by passive diffusion, transporters are obligatory for acceptable oral absorption/bioavailability. Uptake transporters on the membrane of the enterocytes that faces intestinal lumen (apical) and efflux transporters on the membrane that is in contact with blood capillaries (basolateral) mediate a vectorial transport for anionic and zwitterionic compounds, whereas only the apical uptake transporters are involved in the absorption of cationic compounds because of the absence of any efflux transporters for cationic compounds on the basolateral membrane of enterocytes. Efflux transporters on the apical membrane of enterocytes attenuate intestinal absorption of cationic, anionic, and zwitterionic drugs. The uptake and efflux transporters in the intestinal epithelium have significant implications in drug absorption as well as drug-drug and drug-diet interactions, which will be discussed.

Dr. Dhiren R. Thakker is the Ferguson Distinguished Professor and Associate Dean for Economic Development and International Partnerships at the UNC Eshelman School of Pharmacy, the University of North Carolina at Chapel Hill. From 1998 to 2008, he served as the Associate Dean for Research and Graduate Education. He is a co-founder of Qualyst, a company formed based on the technologies invented at the UNC Eshelman School of Pharmacy, UNC-Chapel Hill; in addition, he has also co-founded a drug discovery-development company, Sphaera Pharma.

Prior to joining UNC in 1996, Dr. Thakker spent (i) eight years at Glaxo Inc. where he was Director of Drug Metabolism Department, (ii) four years at the Center for Biologics, FDA, and (iii) eight years at the National Institutes of Health. He obtained Batchelor of Pharmacy from Bombay University, India, M.S. in Pharmaceutical Chemistry from Columbia University, New York, and Ph.D. in Biochemistry from the University of Kansas at Lawrence.

Dr. Thakker’s current research interests are (i) mechanisms of drug transport across intestine, (ii) novel intestinal absorption mechanism and pharmacology of metformin as antidiabetic and anti-cancer drug, (iii) design of absorption enhancers via epithelial tight junction regulation, and (iv) optimizing pediatric dosing by study of drug metabolism and transport in children and adults. In the past he has worked on methyl transferase enzymology, stereoselectivity of cytochrome P-450 enzymes, chemical carcinogenesis and metabolic activation of polycyclic aromatic hydrocarbons. He has published over 160 peer reviewed papers, reviews and book chapters and co-edited two books.

Honors, awards and professional service

  • Sato Memorial Award, the Pharmaceutical Society of Japan
  • Fellow of the American Association of Pharmaceutical Scientists
  • Editorial board, J Pharm Sci
  • Board of Directors and Scientific Advisory Board, Chesson Labs, Durham, NC
  • Chair, Board of Directors, Tergus Pharma, Durham, NC
  • Co-founder and Chair of the Scientific Advisory Board of Sphaera Pharma, U.S.A./India/Singapore
  • Advisory Board, the Office of Technology Development, UNC-Chapel Hill
  • International Affairs Advisory Council, UNC Global, UNC-Chapel Hill
  • IntraHealth Advisory Council – IntraHealth International

Previously held offices

  • Chair, Drug Metabolism Focus Group, AAPS (2010-2012)
  • Editorial board of Drug Metabolism and Disposition
  • Editorial board of Current Drug Metabolism
  • Co-editor, Medicinal Research Reviews
  • Special Emphasis Panel of NIGMS for Program Project review
  • Drug Development Advisory Board, Scios Inc., a J & J company
  • Drug Discovery Interface Task Force, AAPS
  • Advisory Board, the Office of Economic and Business Development, UNC Chapel Hill, 2008-2011
  • Board of Directors and Scientific Advisory Board, Qualyst Inc., Research Triangle Park, NC