Newcastle University

Qualifications

B.Sc Hons Physiology University of St Andrews
Ph.D Physiology University of St Andrews

Previous Positions

Royal Society Euopean Exchange Scheme Postdoctoral Fellow
Institute for Physiology University of Zurich

Wellcome Senior Research Fellow in Biomedical Sciences
Department of Medicine University of Manchester

Memberships

Physiological Society

American Physiological Society

American Association of Pharmaceutical Scientists

Research Interests

Epithelial Transport
Renal, Hepatic and GI drug transporters
Expression Cloning of Organic Anion Transporters
Transporter mediated drug-drug interactions.
Functional impact of allelic variations in transporters upon drug disposition
Drug screening through a panel of hepatic and renal cloned transporters

Development of primary renal cell models to study species variation in ADMET

The key objectives of my laboratory are to: (i) Generate and characterise a human, rat, mouse and dog primary proximal tubule model as an in vitro platform for drug safety studies (ii) measure species differences in the handling of key molecules between rat, mouse, dog and human kidney proximal tubule cells to predict human toxicity. (iii) Generate in vitro – in vivo correlations for the handling of a range of drug molecules of diverse chemistries and renal clearance rates in each model. (iiv) Understand which transporters at the apical and basolateral membrane of human proximal tubule cells are key in determining the renal handling of a candidate molecule and therefore present targets for drug-drug interactions which may change the pharmacokinetics and toxicokinetics of renal drug elimination in either species.
There are 2 key outcomes from this work: Firstly it would be possible to gain clear unambiguous transport data on the handling of candidate drug molecules in rat which is a key species in drug development/drug safety and secondly it would generate the ability to compare, at an early stage, the handling of molecules in very similar in-vitro models derived from rat, mouse, dog and human kidney. With these screening platforms in place, not only would there be an in vitro platform to investigate drug handling in multi- species, but crucially, direct comparison of the renal handling of a molecule between rat/mouse/dog and human kidney would flag up differences in handling that might impact on the progress of a candidate drug molecule into a pre clinical animal study

Industrial Relevance

 In collaboration with Abcellute Tissue Bank  we are able to supply  Human renal cell monolayers or provide a CRO service:    http://www.abcellutetissuebank.org/our-products/kidney-aproximate/ 

• Hill CR, Jamieson D, Thomas HD, Brown CDA, Boddy AV, Veal GJ. Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo. Biochemical Pharmacology 2013, 85(1), 29-37.
• Jenkinson SE, Chung GW, van Loon E, Bakar NS, Dalzell AM, Brown CDA. The limitations of renal epithelial cell line HK-2 as a model of drug transporter expression and function in the proximal tubule. Pflügers Archiv European Journal of Physiology 2013, (epub ahead of print).
• Dalzell AM, Mistry P, Wright J, Williams FM, Brown CDA. Characterisation of the transport of avermectins by MDR1/Mdr1a and MRP efflux transporters in human SH-SY5Y and mouse N2a neuroblastoma cell lines. Toxicology & Apllied Pharmacology 2012. Submitted.
• Jenkinson SE, Brown C. Drug transporter expression and function in primary cultures of human renal epithelial cells. In: Experimental Biology Meeting. 2012, San Diego, California, USA: Federation of American Societies for Experimental Biology.
• Rigas AC, Williamson SC, Kennedy A, El-Sherif A, Soomro NA, Brown CDA, Robson CN, Heer R. Renal differentiation from adult spermatogonial stem cells. In: Annual Meeting of the Society of Academic and Research Surgery. 2012, Nottingham, UK: John Wiley & Sons Ltd.
• Jenkinson SE, van Loon E, Dalzell A, Brown C. Does the HK2 cell line represent a suitable model for the study of drug transporter expression by renal epithelial cells?. In: Experimental Biology Meeting 2011. 2011, Walter E Washington Convention Center, Washington, DC: Federation of American Societies for Experimental Biology.
• Betteley K, Windass AS, Mutch E, Brown CDA, Williams FM. Characterisation of pesticide transport in neural cells. In: Toxicology: Annual Congress of the British Toxicological Society. 2009, Coventry, UK: Elsevier Ireland Ltd.
• Brown CDA, Sayer R, Windass AS, Haslam IS, De Broe ME, D'Haese PC, Verhulst A. Characterisation of Human proximal tubule cell monolayers as a model of proximal renal xenobiotic secretion. Toxicology and Applied Pharmacology 2008, 233(3), 428-438.
• Betteley KA, Windass AS, Williams FM, Mutch EC, Brown CDA. Characterisation of pesticide transport in SHSY-5Y neuroblastoma cells. In: 2nd Asian Pacific Regional ISSX Meeting. 2008, School of Pharmacy, Fudan University, Shanghai, China: Drug Metabolism Reviews: Informa Healthcare.
• Verhulst A, Sayer R, De Broe ME, D'Haese PC, Brown CDA. Human proximal tubular epithelium actively secretes but does not retain rosuvastatin. Molecular Pharmacology 2008, 74(4), 1084-1091.
• Windass A, Lowes S, Wang Y, Brown C. The contribution of Organic Anion Transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. Journal of Pharmacology and Experimental Therapeutics 2007, 322(3), 1221-1227.
• Simonson S, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CDA, Windass AS, Schneck DW. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clinical Pharmacology and Therapeutics 2004, 76(2), 167-177.
• Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, Lasseter KC, Brown CDA, Windass AS, Raza A. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clinical Pharmacology and Therapeutics 2004, 75(5), 455-463.
• Brown CD, Chauhan S. Functional characterisation of endogenous organic cation transporters expressed by Hela cells. In: FASEB Journal: Experimental Biology Meeting. 2003, San Diego, California, USA: Federation of American Societies for Experimental Biology.
• Brown CD, Chauhan S. Na+ dependent MPP+ uptake across the apical membrane of Caco-2 cells is not mediated by hOCTN2 [abstract]. FASEB Journal 2002, 16(4), A60.
• Chauhan S, Brown CD. Differential expression of hOCT1, hOCT2 and hOCTN2 along the human gastrointestinal tract. In: FASEB Journal. 2001, Federation of American Societies for Experimental Biology.
• Kose H, Boese SH, Glanville M, Gray MA, Brown CDA, Simmons NL. Bradykinin regulation of salt transport across mouse inner medullary collecting duct epithelium involves activation of a Ca2+ -dependent Cl- conductance. British Journal of Pharmacology 2000, 131(8), 1689-1699.
• Chauhan S, Lauffart B, Brown CDA. Characterisation of a novel Na+-dependent organic cation transporter in HeLa cells. In: JOURNAL OF PHYSIOLOGY-LONDON. 2000.
• Bleasby K, Chauhan S, Brown CDA. Characterization of MPP+ secretion across human intestinal Caco-2 cell monolayers: Role of P-glycoprotein and a novel Na+-dependent organic cation transport mechanism. British Journal of Pharmacology 2000, 129(3), 619-625.
• Bleasby K, Lauffart B, Clark MA, Brown CDA. Dids sensitive uptake of cimetidine mediated by an epitope tagged version of the human organic cation transporter hOCT2. In: FASEB JOURNAL. 2000.
• Bleasby K, Green R, Brown CDA. Functional characterisation of the mouse organic cation transporter mOCT1 in HeLa cells. In: JOURNAL OF PHYSIOLOGY-LONDON. 2000.
• Bleasby K, Brown CDA. Handling of beta-adrenoreceptor antagonists by an epitope-tagged version of the human organic cation transporter hOCT2. In: JOURNAL OF PHYSIOLOGY-LONDON. 2000.
• Dudley AJ, Bleasby K, Brown CDA. The organic cation transporter OCT2 mediates the uptake of β-adrenoceptor antagonists across the apical membrane of renal LLC-PK1 cell monolayers. British Journal of Pharmacology 2000, 131(1), 71-79.
• Brown C.D.A. and Dudley A.J. Chloride channel blockers decrease intracellular pH in cultured renal epithelial LLC-PK1 cells. British Journal of Pharmacology 1996, 118, 443-444.
• Dudley A.J. and Brown C.D.A. Cimetidine secretion across epithelial monolayers of LLC-PK1 cells: involvement of 2 distinct transport mechanisms at the apical membrane. British Journal of Pharmacology 1996, 117, 1139-1144.
• Thwaites DT, McEwan GTA, Brown CDA, Hirst BH, Simmons NL. L-Alanine absorption in human intestinal cells driven by the proton electrochemical gradient. Journal of Membrane Biology 1994, 140(2), 143-151.
• Thwaites DT, Brown CDA, Hirst BH, Simmons NL. H⁺-coupled dipeptide (glycylsarcosine) transport across apical and basal borders of human intestinal Caco-2 cell monolayers display distinctive characteristics. Biochimica et Biophysica Acta: Biomembranes 1993, 1151(2), 237-245.
• Thwaites DT, McEwan GTA, Brown CDA, Hirst BH, Simmons NL. Na⁺-independent, H⁺-coupled transepithelial beta-alanine absorption by human intestinal Caco-2 cell monolayers. Journal of Biological Chemistry 1993, 268, 18438-18441.
• Thwaites DT, Brown CDA, Hirst BH, Simmons NL. Transepithelial glycylsarcosine transport in intestinal Caco-2 cells mediated by expression of H⁺-coupled carriers at both apical and basal membranes. Journal of Biological Chemistry 1993, 268(11), 7640-7642.