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School of Pharmacy and Pharmaceutical Sciences

Professor Brian Houston BSc, PhD, DSc

Photograph of Brian Houston

Professor of Drug Metabolism and Phamacokinetics

School of Pharmacy and Pharmaceutical Sciences
Room 3.33, Stopford Building
Oxford Road
Manchester
M13 9PT

 

Role

Director of Centre for Applied Pharmacokinetic Research and Group Leader of Drug Metabolism and Pharmacokinetic Research Group in School of Pharmacy and Pharmaceutical Sciences

 

Research

The Centre for Applied Pharmacokinetic Research (CAPKR) provides an international lead in the development, evaluation and implementation of in vitro and in silico approaches for predicting human pharmacokinetics. Pharmacokinetics plays a pivotal role in drug discovery, development and use since it widely recognised that being bioactive is not enough to ensure therapeutic success. Knowledge on how a drug enters and is processed by the body is as critical as knowledge as its interaction with target sites. Even today many promising drug candidates fail to make it through drug development due to poor pharmacokinetic properties such as inadequate absorption, poor stability, excessive interaction with other drugs. Other drugs are prematurely withdrawn from the market due to toxicities arising from pharmacokinetic idiosyncrasies.

CAPKR’s aim is to improve prediction at all steps between drug discovery and use with mechanism-based modelling methodologies. Major advances have been made in delineating the science that underpins the development and evaluation of paradigms for human prediction. Research activities include, prediction of drug metabolic clearance, molecular and kinetic basis of drug-drug interactions, pharmacokinetic and statistical modelling. Our use of human tissue, and validated surrogates such as recombinant proteins together with computer simulation and modelling are in sympathy with the current ethical and political pressures to reduce, refine and replace the use of animals in research.

Prediction of Drug Clearance in Humans
Drug metabolism and pharmacokinetics (DMPK)  play a pivotal role in drug discovery, development and use. Often drug development is halted or use limited by poor PK properties, mainly drug clearance. We are developing paradigms for the quantitative prediction of human drug clearance through the comprehensive use of different in vitro systems to delineate interactions between the cytochrome P450 and UDP-glucuronyltransferase enzymes and other cellular processes (including permeability and transporter properties). We are particularly interested in the atypical kinetics shown by CYP3A enzymes, the need to incorporate variability and uncertainty within the extrapolation process and transporter-mediated clearance.

Molecular and kinetic basis of Drug-Drug Interactions
In the era of polypharmacy, drug-drug interactions are of major concern and continue to result in drugs being within drawn from the commercial market. We are interested in inhibition of CYP enzymes as the major cause of drug-drug interactions and the ability of simple in vitro systems to predict this effect. We are assessing the modelling of time dependent inhibition, multiple DDIs, transporter involvement and induction effects.

Research links

 

Teaching

  • Drug Toxicity
  • Drug Metabolism and Disposition
  • Pharmacokinetics
  • Biopharmaceutics
 

Biography

Brian obtained his BSc, PhD and DSc from the Universities of London (Queen Mary College), Surrey and Manchester, respectively. He is currently Professor of Drug Metabolism and Pharmacokinetics within the School of Pharmacy and Pharmaceutical Sciences. His research is sponsored by a number of sources including the pharmaceutical industry, BBSRC, DoH and the EU.

Brian is Director of the Centre for Applied Pharmacokinetic Research within the School of Pharmacy. This involves four faculty members and supports twenty research staff. As a consortium it operates in collaboration with, and financially supported by five international pharmaceutical companies. All research is generic and involves the prediction of human pharmacokinetics.

Brian is a member of the editorial boards of several scientific journals, has experience on national science funding bodies and is a consultant to a number of pharmaceutical companies.

In recent years he has been particularly active through his research and numerous conference presentations in promoting the use of in vitro and in silico systems for predicting human metabolism and pharmacokinetics.

 

Qualifications

  • 1997 - DSc (Manchester)
  • 1973 - PhD (Surrey)
  • 1970 - BSc (Queen Mary College, London)
 

Collaborators and affiliated staff

CAPKR Collaboration

Leon Aarons

Aleksandra Galetin

David Hallifax

Amin Rostami

Jeff Penny

Postdoctoral Research Associates

C Cantrill, M Gertz

PhD Students

K Menochet, S Tate, C Lager, K Gill,  A Ufuk and R Sullivan

Research Technican

S Murby

External Collaborators

John Miners

Simcyp Ltd

 

Selected publications

2011

  • Cubitt HE, Houston JB, Galetin A. (2011). Prediction of human drug clearance by multiple metabolic pathways: integration of hepatic and intestinal microsomal and cytosolic data. Drug Metab Dispos, 39(5), 864-73. eScholarID:132503 | DOI:10.1124/dmd.110.036566
  • Gertz M, Houston JB, Galetin A. (2011). Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction. Drug Metab Dispos, 39(9), 1633-1642. eScholarID:132526 | DOI:10.1124/dmd.111.039248
  • Graham Lappin, Yoko Shishikura, Roeline Jochemsen, Richard John Weaver, Charlotte Gesson, J. Brian Houston, Berend Oosterhuis, Ole J. Bjerrum, Grzegorz Grynkiewicz, Jane Alder, Malcolm Rowland, Colin Garner. (2011). Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers. European Journal of Pharmaceutical Sciences, 43, 141-150. eScholarID:123462 | DOI:10.1016/j.ejps.2011.04.009
  • Guest EJ, Aarons L, Houston JB, Rostami-Hodjegan A, Galetin A. (2011). Critique of the two-fold measure of prediction success for ratios:application for the assessment of drug-drug interactions. Drug Metab Dispos, 39(2), 170-173. eScholarID:95952 | DOI:10.1124/dmd.110.036103
  • Guest EJ, Rowland-Yeo K, Rostami-Hodjegan A, Tucker GT, Houston JB, Galetin A. (2011). Assessment of Algorithms for Predicting Drug-Drug Interactions via Inhibition Mechanisms: Comparison of Dynamic and Static Models. Br J Clin Pharmacol, 71(1), 72-87. eScholarID:95959 | DOI:10.1111/j.1365-2125.2010.03799.x
  • Joanne A. Foster, J. Brian Houston, David Hallifax. (2011). Comparison of intrinsic clearances in human liver microsomes and suspended hepatocytes from the same donor livers: clearance-dependent relationship and implications for prediction of in vivo clearance. Xenobiotica, 41, 124-136. eScholarID:95954 | DOI:10.3109/00498254.2010.530700
  • Menochet K, Kenworthy KE, Houston JB, Galetin A. (2011). Simultaneous Assessment of Uptake and Metabolism in Rat Hepatocytes: A Comprehensive Mechanistic Model. doi:10.1124/jpet.111.187112. J Pharmacol Exp Ther, eScholarID:147629
  • Templeton IE, Houston JB, Galetin A. (2011). Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells. Drug Metab Dispos, 39(10), 1921-1929. eScholarID:132529 | DOI:10.1124/dmd.111.040824
  • Yabe Y, Galetin A, Houston JB. (2011). Kinetic characterization of rat hepatic uptake of 16 actively transported drugs. Drug Metab Dispos, 39(10), 1808-1814. eScholarID:132532 | DOI:10.1124/dmd.111.040477

2010

  • Galetin A, Houston JB. (2010). Inhibition of Drug Metabolizing Enzymes in Gastrointestinal Tract and its Influence on the Drug-Drug Interaction Prediction, in Enzyme Inhibition in Drug Discovery and Development. In C. Lu and A. P. Li, eds (Ed.), (pp. 315-343). John Wiley. eScholarID:3d924
  • Houston JB and Galetin A. (2010). In vitro techniques to study drug-drug interactions of drug metabolism: Cytochrome P450. In Pang KS, Rodrigues AD, Peter RM (Ed.), Enzymatic and Transporter Based Drug-Drug Interactions: Progress and Future Challenges. (pp. 169-215). USA: Springer. eScholarID:79991
  • JB Houston. (2010). Development of physiological models incorporating transporter and enzyme interplay for clearance and DDI prediction. Presented at Gordon Conference on Drug Metabolism. Holderness, NH, USA. eScholarID:96035
  • JB Houston. (2010). Transporters and cytochrome P450 interplay in defining hepatic drug clearance. Presented at 4th European Cyprotex Drug Discovery Workshop. London. eScholarID:96034
  • Menochet K, Kenworthy K, Houston JB and Galetin A. (2010). Contribution of active uptake to the hepatic clearance of seven OATP substrates in rat and human plated hepatocytes. Presented at DMDG Meeting. Canterbury. eScholarID:107120
  • Tate S, Jones HM, Houston JB and Galetin A. (2010). Physiologically-based pharmacokinetic modelling of hepatic transporter substrate rosuvastatin. Presented at DMDG Meeting. Canterbury. eScholarID:107122
  • (2010). Application of different in vitro systems for prediction of in vivo induction drug-drug interactions. Presented at 9th International ISSX Meeting. Istanbul, Turkey. eScholarID:96040
  • (2010). Contribution of active uptake to the hepatic clearance of seven OATP substrates in rat and human plated hepatocytes. Presented at 9th International ISSX Meeting. Istanbul, Turkey. eScholarID:96042
  • (2010). Drug clearance in different in vitro systems as a preliminary indicator of hepatic uptake. Presented at 9th International ISSX Meeting. Istanbul, Turkey. eScholarID:96043
  • (2010). Physiologically-based pharmacokinetic modelling approach to assess the uptake transporter-mediated drug-drug interaction potential of cyclosporine. Presented at 9th International ISSX Meeting. Istanbul, Turkey. eScholarID:96041
  • Zanelli, U, Caradonna, NP, Hallifax, D, Houston, JB. (2010). Prediction of clearance from the HepaRG cell system: comparison with human hepatocytes for a range of substrates. Presented at 9th International ISSX Meeting. Istanbul, Turkey. eScholarID:96039
  • Burt HJ, Galetin A, Houston JB. (2010). IC50-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4. Xenobiotica, 40(5), 331-43. eScholarID:79989 | DOI:10.3109/00498251003698555
  • Galetin A, Gertz M and Houston JB. (2010). Contribution of intestinal cytochrome P450-mediated metabolism to drug-drug inhibition and induction interactions. Drug Metab Pharmacokinet, 25(1), 28-47. eScholarID:79988 | DOI:10.2133/dmpk.25.28
  • Graham Lappin, Yoko Shishikura, Roeline Jochemsen, Richard J Weaver, Charlotte Gesson, Brian Houston, Berend Oosterhuis, Ole J Bjerrum, Malcolm Rowland and Colin Garner. (2010). Pharmacokinetics of fexofenadine: Evaluation of a microdose and assessment of absolute oral bioavailability. European Journal of Pharmaceutical Sciences, 40, 125-131. eScholarID:112741 | DOI:10.1016/j.ejps.2010.03.009
  • Hallifax, D, Foster, JA and Houston, JB. (2010). Prediction of human metabolic clearance from in vitro systems: retrospective analysis and prospective view. Pharmaceutical Research, 27, 2150-2161. eScholarID:95060 | DOI:10.1007/s11095-010-0218-3
  • HS Brown, AJ Wilby, J Alder and JB Houston. (2010). Comparative use of isolated hepatocytes and hepatic microsomes for cytochrome P450 inhibition studies: Transporter-enzyme interplay. Drug Metab Dispos, 38, 2139-2146. eScholarID:95973 | DOI:10.1124/dmd.110.035824
  • Michael Gertz, Anthony Harrison, J Brian Houston and Aleksandra Galetin. (2010). Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Dispos, 38, 1147-1158. eScholarID:85103 | DOI:10.1124/dmd.110.032649
  • MT Donato, D Hallifax, L Picazo, JV Castell, JB Houston, M-J Gomez-Lechon, and A Lahoz. (2010). Metabolite formation kinetics and intrinsic clearance of phenacetin, tolbutamide, alprazolam and midazolam in adenoviral P450 transfected HepG2 cells and comparison with hepatocytes and in vivo. Drug Metab Dispos, 38(9), 1449-1455. eScholarID:83383 | DOI:10.1124/dmd.110.033605

2009

  • Burt H, Carolina Lager, Ruth Hyland, Houston B, Galetin A. (2009). A progress curve approach for the assessment of time-dependent inhibition of CYP3A4. eScholarID:2d2579
  • Foster JA, Hallifax D, Houston B. (2009). How good is prediction of in vivo metabolic clearance from established in vitro systems?. Presented at 10th European ISSX Meeting. Lisbon, Portugal. eScholarID:2d2570
  • Guest EJ, Rowland Yeo K, Rostami-Hodjegan A, Tucker GT, Houston JB and Galetin A. (2009). Assessment of Algorithms for Predicting Drug-Drug Interactions via Inhibition Mechanisms. Presented at Drug Metabolism Discussion Group (DMDG) Meeting. Cambridge. eScholarID:107126
  • JB Houston. (2009). Transporters and cytochrome P450 interplay in defining hepatic drug clearance. Presented at Citocromo P450: Aspetti Farmacologici, Tossicologici Ed Ambientali. Siena, Italy. eScholarID:116684
  • Jigorel EE, Houston B. (2009). Involvement of drug uptake in hepatic clearance. eScholarID:2d2226
  • Tate S, Jones HM, Houston JB and Galetin A. (2009). . Physiologically-Based Pharmacokinetic Modelling of Hepatic Uptake of Pravastatin and Rosuvastatin. Presented at PKUK meeting. Birmingham. eScholarID:107132
  • Badhan RK, Penny J, Galetin A, Houston JB. (2009). Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption. J Pharm Sci, 98(6), 2180-2197. eScholarID:1d18097
  • Hallifax D, Houston B. (2009). Methodological uncertainty in quantitative prediction of human hepatic clearance from in vitro experimental systems. Current Drug Metabolism, 307-321. eScholarID:1d19091
  • HE Cubitt, Houston JB, Galetin A. (2009). Relative Importance of Intestinal and Hepatic Glucuronidation-Impact on the Prediction of Drug Clearance. Pharm Res, 26, 1073-1083. eScholarID:1d18777 | DOI:10.1007/s11095-008-9823-9
  • PJ Kilford, R Stringer, B Sohal, Houston B, Galetin A. (2009). Prediction of Drug Clearance by Glucuronidation from in Vitro Data: Use of Combined Cytochrome P450 and UDP-Glucuronosyltransferase Cofactors in Alamethicin-Activated Human Liver Microsomes. Drug Metab Dispos, 37, 82-89. eScholarID:1d18775 | DOI:10.1124/dmd.108.023853
  • Rowan A Stringer, Claire Strain-Damerell, Paul Nicklin, Houston JB. (2009). Evaluation of recombinant P450 enzymes as an in vitro system for metabolic clearance predictions. Drug Metab Dispos, 37, 1025-1034. eScholarID:1d18770 | DOI:10.1124/dmd.108.024810

2008

  • Hallifax D, Galetin A, Houston B. (2008). Prediction of metabolic clearance using fresh human hepatocytes: Comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines. Xenobiotica, 38, 353-367. eScholarID:1d17249 | DOI:10.1080/00498250701834665
  • Laura Hinton, Galetin A, Houston JB. (2008). Multiple inhibition mechanisms and prediction of Drug-Drug Interactions: Status of Metabolism and Transporter Models as Exemplified by Gemfibrozil-Drug Interactions. Pharmaceutical Research, eScholarID:1d16778 | DOI:10.1007/s11095-007-9446-6
  • Michael Gertz, John D Davis, Anthony Harrison, Houston B, Galetin A. (2008). Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations. Curr Drug Metab, 9, 785-795. eScholarID:1d18096 | DOI:10.2174/138920008786049276

2007

  • Brown H, Anthony Chadwick, Houston B. (2007). Use of isolated hepatocyte preparations for cytochrome P450 inhibition studies: comparison with microsomes for Ki determination. Drug Metabolism and Disposition, 35(11), 2119-2126. eScholarID:1d16785
  • Brown H, M Griffin, Houston B. (2007). Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance. Drug Metabolism and Disposition, 35, 293-301. eScholarID:1d15120
  • Galetin A, Laura Hinton, Howard Burt, Houston B. (2007). Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug-drug interactions for CYP3A4 cleared drugs. Current Drug Metabolism, 8, 685-693. eScholarID:1d16777
  • Hallifax D, Houston JB. (2007). Saturable uptake of lipophilic amine drugs into isolated hepatocytes: Mechanisms and consequences for quantitative clearance prediction. Drug Metab Dispos, 35, 1325-1332. eScholarID:1d16101
  • Nicola J Hewitt, Maria Jose Gomez Lechon, Houston, B, Hallifax, D, Brown, H, Patrick Maurel, J Gerald Kenna, Lena Gustavasson, Christina Lohmann, Christian Skonberg, Andre Guillouzo, Gregor Tuschl, Albert P Li, Edward LeCluyse. (2007). Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance and hepatotoxicity studies. Drug Metabolism Reviews, 39, 159-234. eScholarID:1d15579

2006

  • Brown H, Galetin A, Hallifax D, Houston J B. (2006). Prediction of in vivo drug-drug interactions from in vitro data: prototypic drug-drug interactions involving CYP2C9, CYP2D6 and CYP3A4. Clinical Pharmacokinetics, 45, 1035-1050. eScholarID:1d14359
  • Galetin A, Burt H, Gibbons L, Houston J.B. (2006). Prediction of time-dependent CYP3A4 drug-drug interactions: impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition. Drug Metabolism Disposition, 34, 166-175. eScholarID:1d12869 | DOI:10.1124/dmd.105.006874
  • Galetin A, Houston B. (2006). Intestinal and hepatic metabolic activity of five cytochrome P450 enzymes: Impact on prediction of first-pass metabolism. The Journal of Pharmacology and Experimental Therapeutics, 318, 1220-1229. eScholarID:1d13656
  • Hallifax D, Houston B. (2006). Uptake and intracellular binding of lipophilic amine drugs by isolated rat hepatocytes and implications for prediction of in vivo metabolic clearance. Drug Metabolism and Disposition, 34, 1829-1836. eScholarID:1d15121
  • Hallifax D, Houston JB. (2006). Binding of drugs to hepatic microsomes: comment and assessment of current prediction methodology with recommendation for improvement. Drug Metabolism Disposition, 34, 724-726. eScholarID:1d12867
  • J O Miners, J M Knights, Houston B, P I MacKenzie. (2006). In vitro-in vivo correlation for drugs and compounds eliminated by hepatic glucuronidation in humans: Pitfalls and promises. Biochem Pharmacol, 71, 1531-1539. eScholarID:1d16786
  • R Scott Obach, Robert L Walsky, Karthik Venkatakrishnan, Emily A Gaman, Houston B, Larry M Tremaine. (2006). The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. The Journal of Pharmacology and Experimental Therapeutics, 316, 336-348. eScholarID:1d12870

2005

  • Galetin A, Howard Burt, Houston B. (2005). Prediction of time-dependant drug-drug interactions - impact of parallel pathways, enzyme degradation and intestinal inhibition. eScholarID:2d2234
  • Galetin A, Kiyomi Ito, Hallifax D, Houston J.B. (2005). CYP3A4 Substrate selection and substitution in the prediction of potential drug-drug interactions. Journal of Pharmacology and Experimental Therapeutics, 314, 180-190. eScholarID:1d11047 | DOI:10.1124/jpet.104.082826
  • Hallifax D, Helen Rawden, Nancy Hakooz, Houston J.B. (2005). Prediction of metabolic clearance using cryopreserved human hepatocytes: kinetic characteristics and liver variability for five benzodiazepines. Drug Metabolism Disposition, 33, 1-7. eScholarID:1d11363 | DOI:10.1124/dmd.105.005389
  • Helen Rawden, David Carlile, Andrew Tindall, Hallifax D, Galetin A, Kiyomi Ito, Houston J.B. (2005). Microsomal prediction of in vivo clearance and associated inter individual variability of six benzodiazepines in humans. Xenobiotica, 35, 603-625. eScholarID:1d11359 | DOI:10.1080/00498250500162870
  • Ito K, Houston J.B. (2005). Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharmaceutical Research, 22, 103-112. eScholarID:1d10414 | DOI:10.1007/s11095-004-9015-1
  • K Ito, D Hallifax, RS Obach, JB Houston. (2005). Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement in drug-drug interactions: CYP2D6 paradigm. Drug Metab Dispos, 33, 837-844. eScholarID:1d11048 | DOI:10.1124/dmd.105.003715
  • R Scott Obach, Robert L Walsky, Karthik Venkatakrishnan, Houston B, Larry M Tremaine. (2005). In vitro cytochrome P450 inhibition data and the prediction of drug-drug interactions: qualitative relationships, quantitative predictions, and the rank-order approach. Clin Pharmacol Ther, 78, 589-92. eScholarID:1d12871

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