Dr Colin Brown
- Email: email@example.com
- Telephone: +44 (0) 191 208 7036
- Fax: +44 (0) 191 208 7424
- Personal Website: http://research.ncl.ac.uk/epithelia/
- Address: Institute for Cell and Molecular Biosciences
Newcastle upon Tyne
B.Sc Hons Physiology University of St Andrews
Ph.D Physiology University of St Andrews
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
American Physiological Society
American Association of Pharmaceutical Scientists
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
Human proximal tubule cells - strategic alliance with Solvo Biotechnology.
Human proximal tubule cells are available for drug screening projects via Solvo Biotechnology
Renal drug handing and drug-drug interactions screening service
Nine out of ten new drugs which enter clinical testing will fail and most of these will be during Phase II studies despite these new drugs performing well in pre-clinical studies. In vitro ADMET assays exist to provide essential data on how new drugs will be transported by the kidney. The assays currently offered by Contract Research Organisations (CROs) are based on human or animal cells transfected to express single or dual human kidney transporters on their surfaces. The major limitation with these assays is that they do not accurately reflect the situation in vivo where there may be more than one transporter involved in the drug handling or when there is competition with other drug molecules. Thus the current assays do not accurately predict drug handling or nephrotoxicity in the clinical setting.
Thus new drugs entering clinical trials will often behave in an unexpected manner when faced with intact proximal tubule cells.
Dr Brown is the leading expert on drug transport in human kidney and has optimised a primary kidney proximal tubule cell (KPTC) model for the investigation of drug handling and nephrotoxicity (the a-Proximate system). The a-Proximate system is available using primary human, rat or mouse KPTC. The a-Proximate system offers a superior alternative to commerically available cloned transporter assays as it can be used to accurately predict renal drug handling and drug-drug interactions prior to clinical trials.
The a-Proximate system offers a bespoke service for clients including;
· flux measurement
· net transport
· monitoring of paracellular flux
· intracellular measurement of drug and metabolites
· mechanistic analysis of individual in disposition of the drug
· identification of transporter medicated drug-drug interactions
· identification of potential nephrotoxicity using a panel of early markers of damage
· suitable for use in early drug discovery
· KPTC are isoalted from fresh normal kidney, less than 12 hours ex vivo
· Cells are grown on permeable filter HTS Transwell membranes to generate fully functional differentiated monolayers with TEER of ~140-180Ω .cm2
· Available in 12 and 24 well formats
· Transporters expressed at the Apical membrane- MDR1, MRP2, MRP4, MRP1, BCRP, MATE, OAT4, OCTN1, OCTN2, NaPi2a
· Transporters expressed at the Basolateral membrane- OAT1, OAT2, OAT3, OCT2, OCT3, OATP4C1, NBC.
· Transporter function has been validated using a wide range of drug molecules of diverse in vivo renal clearance.
Brown CDA; Sayer R; Windass AS; Haslam IS; De Broe ME; D'Haese PC; Verhulst A (2008). Toxicol & Applied Pharmacol, 233: 428-438.
Huls M; Brown CDA; Windass AS; Sayer R; Van Den Heuvel JJMW; Heemskerk S; Russel FGM; Masereeuw R. (2008) Kid Int, 73: 220-225.
- Chaudhry A, Chung G, Lynn A, Yalvigi A, Brown C, Ellens H, O'Connor M, Lee C, Bentz J. Derivation of a system-independent Ki for Pgp-mediated digoxin transport from system-dependent IC50 data by accounting for the contribution of additional digoxin transporters. Drug Metabolism and Disposition 2018, (ePub ahead of Print).
- Scotcher D, Billington S, Brown J, Jones CR, Brown CDA, Rostami-Hodjegan A, Galetin A. Microsomal and Cytosolic Scaling Factors in Dog and Human Kidney Cortex and Application for In Vitro-In Vivo Extrapolation of Renal Metabolic Clearance. Drug Metabolism and Disposition 2018, 45(5), 556-568.
- Bakar NS, Neely D, Avery P, Brown C, Daly AK, Kamali F. Genetic and Clinical Factors Are Associated With Statin-Related Myotoxicity of Moderate Severity: A Case–Control Study. Clinical Pharmacology and Therapeutics 2017, epub ahead of print.
- Prasad B, Johnson K, Billington S, Lee C, Chung GW, Brown CDA, Kelly EJ, Himmelfarb J, Unadkat JD. Abundance of Drug Transporters in the Human Kidney Cortex as Quantified by Quantitative Targeted Proteomics. Drug Metabolism and Disposition 2016, 44(12), 1920-1924.
- Chung GW, Billington SF, Jenkinson SE, Brown CD. Drug transporters in the kidney. In: Nicholls G; Youdim K, ed. Drug Transporters : Volume 1: Role and Importance in ADME and Drug Development. Cambridge: Royal Society of Chemistry, 2016, pp.109-150.
- Bakar NSB, Kamali F, Brown CDA. Effect of Statins on Functional Expression of Membrane Transporters in L6 Rat Skeletal Muscle Cells. Journal of Biomedical and Clinical Sciences 2016, 1(1), 17-26.
- Dalzell AM, Mistry P, Wright J, Williams FM, Brown CDA. Characterization of multidrug transporter-mediated efflux of avermectins in human and mouse neuroblastoma cell lines. Toxicology Letters 2015, 235(3), 189-198.
- Probert PM, Chung GW, Cockell SJ, Agius L, Mosesso P, White SA, Oakley F, Brown CD, Wright MC. Utility of B-13 Progenitor-Derived Hepatocytes in Hepatotoxicity and Genotoxicity Studies. Toxicological Sciences 2014, 137(2), 350-370.
- 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.
- Heer R, Hepburn AC, Williamson SC, Kennedy A, El-Sherif A, Soomro NA, Brown CD, Robson CN. Renal differentiation from adult spermatogonial stem cells. Renal Failure 2013, 35(10), 1387-1391.
- 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, 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 2012, 464(6), 601-611.
- 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 tubular cell monolayers as a model of proximal tubular xenobiotic handling. 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.