Career Scientist, Ontario HIV Treatment Network, Ministry of Health of Ontario
Drug Transport and Therapeutics
Drug transport processes across cell membranes are of pharmacokinetic, pharmacodynamic and therapeutic or toxic significance. It is through these transport mechanisms that: i) drugs have access to the receptor site (target organ) and exert their pharmacological effect; ii) drugs undergo absorption, elimination and/or reabsorption from organs and cellular compartments i.e., gastrointestinal mucosa membrane, hepatocytes, central nervous system (blood-brain barrier and choroid plexus) and renal tubules; and iii) drugs can interact and compete for similar membrane transporters which can ultimately result in toxicity.
Our research program can be divided into two major areas: i) basic studies (in vitro, in situ and in vivo) examining regulation of drug transport in renal, intestinal, testicular and brain tissues and ii) clinical studies investigating drug disposition, drug-drug interactions and drug utilization. In the past few years, the interests of our research have primarily focused in the field of Human Immunodeficiency Virus (HIV) infection of the brain and its pharmacological treatment. Recently, we have expanded the work and included other organs and blood-tissue barriers (gastro-intestinal mucosa, testicular tissues). The objectives of the basic studies are to investigate the molecular expression, cellular/subcellular location and functional activity of putative membrane transporters known to play an important role in the disposition of various antiretroviral compounds (i.e., nucleoside analog compounds, protease inhibitors) in normal physiological conditions as well as in the context of HIV-1 associated inflammatory response. Various in vitro tissue cell culture models (i.e., primary and continuous renal epithelial cells, intestinal cells, testicular Sertoli cells and brain microvessel endothelial cells as well as brain parenchyma cells) isolated from both rodent and human tissues are used in our laboratory for the undertaking of these studies. In addition, in situimmunocytochemistry/immunohistochemistry studies and in vivo drug pharmacokinetic studies are performed. Clinical studies are complementary to the basic studies and explore the significance of drug-drug interactions and patterns of drug use in specific patient populations (i.e., HIV, pediatric and women).
Hoque MT, Shah A, More V, Miller DS, Bendayan R. In vivo and ex vivo regulation of breast cancer resistant protein (Bcrp) by peroxisome proliferator-activated receptor alpha (Pparα) at the blood-brain barrier. J Neurochem. 2015 Oct 14. doi: 10.1111/jnc.13389. [Epub ahead of print]
Ashraf T, Jiang W, Hoque MT, Henderson J, Wu C, Bendayan R. Role of anti-inflammatory compounds in human immunodeficiency virus-1 glycoprotein120- mediated brain inflammation. J. Neuroinflammation. 2014 May 16; 11(1):91:1-14.
Ashraf T, Kao A, Bendayan R. Functional expression of drug transporters in glial cells: potential role on drug delivery to the CNS. Adv. Pharmacol. 2014 Aug 22; 71:45-111.
Kis O, Walmsley SL, Bendayan R. In vitro and in situ evaluation of pH-dependence of atazanavir intestinal permeability and interactions with acid-reducing agents. Pharm Res. 2014 Sep; 31(9):2404-2019.
Robillard KR, Chan GN, Zhang G, la Porte C, Cameron W, Bendayan R. Role of P-glycoprotein in the distribution of the HIV-protease inhibitor, atazanavir, In the brain and male genital tract. Antimicrob Agents Chemother. 2014; 58(3):1713-22.
Hoque MT, Robillard KR, Bendayan R. Regulation of breast cancer resistant protein by peroxisome proliferator-activated receptor α in human brain microvessel endothelial cells. Mol Pharmacol. 2012 Apr; 81(4):598-609.
Kis O; Robillard K, Chan G, Bendayan R. Complexities of antiretroviral drug-drug interactions: role of ABC and SLC Transporters”. Trends in Pharmacological Sciences 2010; 31:22-35.
Ronaldson PT, Ashraf T, Bendayan R. Regulation of MRP1 by Tumor Necrosis Factor–alpha in cultures glial cells: involvement of NFK-B and C-Jun- N-terminal kinase signaling pathways. Mol Pharmacol 77: 644-659, 2010.
Ronaldson P, Persidsky, Bendayan R. Regulation of ABC membrane transporters in glial cells: Relevance to the pharmacotherapy of brain HIV-1 infection. Glia 56: 1711-1735, 2008.
Dr. Bendayan is an active member of the CanCURE (Canadian HIV Cure Enterprise) research consortium.
University of Toronto
144 College Street
Toronto, Ontario, M5S 3M2