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
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.