Professor Brian Houston BSc, PhD, DSc

Photograph of Brian Houston

Professor of Drug Metabolism and Pharmacokinetics

Manchester Pharmacy School
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 and Head of Pharmaceutical Sciences in Manchester Pharmacy School .

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 Other drugs are prematurely withdrawn from the market due to toxicities arising from pharmacokinetic idiosyncrasies.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, F Assmus, T de Bruyn

PhD Students

A Ufuk, R Sullivan, F Wood and J Harrison

Research Technican

S Murby

External Collaborators

John Miners

Simcyp Ltd

Selected publications

2014

  • J B Houston. (2014). Interplay between enzymes and transporters in defining hepatic drug clearance and intracellular concentration of drugs. Presented at Invited talk at The Royal Society of Chemistry. London. eScholarID:220292
  • Dennis Smith, Per Artursson, Alex Avdeef, Li Di, Gerhard F. Ecker, Bernard Faller, J. Brian Houston, Manfred Kansy, Edward H. Kerns, Stefanie D. Krämer, Hans Lennernäs, Han van de Waterbeemd, Kiyohiko Sugano, and Bernard Testa. (2014). Passive Lipoidal Diffusion and Carrier-Mediated Cell Uptake Are Both Important Mechanisms of Membrane Permeation in Drug Disposition. Mol Pharm, 11, 1727-1738. eScholarID:229776 | DOI:10.1021/mp400713v
  • Gertz M, Tsamandouras N, Säll C, Houston JB, Galetin A. (2014). Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk. Pharm Res, eScholarID:225480 | DOI:DOI 10.1007/s11095-014-1333-3
  • Haruka Nishimuta, J B Houston and Aleksandra Galetin. (2014). Hepatic, intestinal, renal and plasma hydrolsis of prodrugs in human, cynomolgus monkey, dog and rat - implications for in vitro-in vivo extrapolation of clearance of prodrugs. D M D, eScholarID:229774 | DOI:10.1124/dmd.114.057372

2013

  • A Ufuk, M Gertz, J Plumb, G Somers, JB Houston and A Galetin. (2013). Drug accumulation in alveolar macrophages: assessment of uptake and lysosomal distribution in vitro. Presented at DMDG. Cambridge, UK. eScholarID:220296
  • J B Houston. (2013). Addressing the challenges of low clearance. Presented at Mini Symposium, AAPS Annual Meeting and Exposition. San Antonio, Texas. eScholarID:220286
  • J B Houston. (2013). Evaluation of novel in vitro systems for low hepatic clearance and assessment of their predictive utility. Presented at AAPS Annual Meeting and Exposition. San Antonio, Texas. eScholarID:220287
  • Gill KL, Gertz M, Houston JB, Galetin A. (2013). Application of a Physiologically-Based Pharmacokinetic Model to Assess Propofol Hepatic and Renal Glucuronidation in Isolation; Utility of In Vitro and In Vivo Data. Drug Metab Dispos. doi:10.1124/dmd.112.050294, 41, 744-753. eScholarID:189684
  • M Gertz, C Cartwright, M Hobbs, K Kenworthy, M Rowland, JB Houston and A Galetin. (2013). Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: Application of PBPK modeling in the assessment of drug-drug interaction potential. Pharm Research doi: 10.1007/s11095-012-0918-y, 30(3), 761-780. eScholarID:179761
  • JB Houston. (2013). Special Section on Prediction of human pharmacokinetic parameters from in vitro systems-Commentary. Drug Metab Dispos, 41, 1973-1974. eScholarID:220295

2012

  • A Ufuk, GI Somers, JB Houston and A Galetin. (2012). In vitro assessment of accumulation of inhaled drugs by alveolar macrophages. Presented at DMDG Open Meeting. Loughborough, UK. eScholarID:220297
  • J B Houston. (2012). Predictive hepatocellular activity: Cornerstone for PBPK modelling (B2). Presented at The University of Rhode Island International Conference. Rhode Island, USA. eScholarID:220289
  • Burt HJ, Pertinez H, Säll C, Collins C, Hyland R, Houston JB and Galetin A. (2012). A progress curve approach for assessing time-dependent inhibition of CYP3A4. Drug Metab Dispos, 40(9), 1658-1667. eScholarID:175381 | DOI:10.1124/dmd.112.046078
  • C Sall, JB Houston and A Galetin. (2012). A comprehensive assessment of repaglinide metabolic pathways: Impact of choice of in vitro system and relative enzyme contribution to in vitro clearance. Drug Metab Dispos, 40(7), 1279-1289. eScholarID:161180 | DOI:10.1124/dmd.112.045286
  • D Hallifax and JB Houston. (2012). Evaluation of hepatic clearance using in vitro data: emphasis on fraction unbound in plasma and drug ionising using a database of 107 drugs. J Pharm Sci, 101(8), 2645-2652. eScholarID:161182 | DOI:10.1002/jps.23202
  • D Hallifax, E Turlizzi, U Zanelli and JB Houston. (2012). Clearance-dependent underprediction of in vivo intrinsic clearance from human hepatocytes: Comparison with permeabilities from artificial membrane (PAMPA) assay, in silico and caco-2 assay for 65 drugs. Drug Metab Dispos, 45, 570-574. eScholarID:161181 | DOI:10.1016/j.ejps.2011.12.010
  • Emilie Jigorel and J. Brian Houston. (2012). Utility of Drug Depletion-Time Profiles in Isolated Hepatocytes for Accessing Hepatic Uptake Clearance: Identifying Rate-Limiting Steps and Role of Passive Processes. DRUG METABOLISM AND DISPOSITION, 40(8), 1596-1602. eScholarID:176783 | DOI:10.1124/dmd.112.045732
  • Gill KL, Houston JB, Galetin A. (2012). Characterization of In Vitro Glucuronidation Clearance of a Range of Drugs in Human Kidney Microsomes: Comparison to Liver and Intestinal Glucuronidation and Impact of Albumin. Drug Metab Dispos, 40(4), 825-835. eScholarID:159148 | DOI:10.1124/dmd.111.043984
  • JB Houston, Karen Rowland-Yeo, Ugo Zanelli. (2012). Evaluation of the novel in vitro systems for hepatic drug clearance and assessment of their predictive utility. Toxicology in Vitro, 26, 1265-1271. eScholarID:181592 | DOI:10.1016/j.tiv.2011.12.016
  • Jones HM, Barton HA, Lai Y, Bi Y, Kimoto E, Kempshall S, Tate SC, El-Kattan A, Houston JB, Galetin A and Fenner KS. (2012). Mechanistic pharmacokinetic modelling for the prediction of transporter-mediated disposition in human from sandwich culture human hepatocyte data. Drug Metab Dispos, 40(5), 1007-1017. eScholarID:159149 | DOI:10.1124/dmd.111.042994
  • L Di, P Artursson, A Avdeef, GF Ecker, B Faller, H Fischer, JB Houston, M Kansy, EH Kerns, SD Kramer, H Lennernas and K Sugano. (2012). Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discovery Today, 17, 905-912. eScholarID:175388 | DOI:10.1016/j.drudis.2012.03.015
  • Ménochet K, Kenworthy KE, Houston JB and Galetin A. (2012). Simultaneous Assessment of Uptake and Metabolism in Rat Hepatocytes: A Comprehensive Mechanistic Model. J Pharmacol Exp Ther, 341(1), 2-15. eScholarID:159147 | DOI:10.1124/jpet.111.187112
  • Ménochet K, Kenworthy KE, Houston JB and Galetin A. (2012). Use of mechanistic modelling to assess inter-individual variability and inter-species differences in active uptake in human and rat hepatocytes. Drug Metab Dispos, 40(9), 1744-1756. eScholarID:165904 | DOI:10.1124/dmd.112.046193
  • Menochet K, Kenworthy KE, Houston JB, Galetin A. (2012). Simultaneous Assessment of Uptake and Metabolism in Rat Hepatocytes: A Comprehensive Mechanistic Model. doi:10.1124/jpet.111.187112. J Pharmacol Exp Ther, 341(1), 2-15. eScholarID:147629
  • U Zanelli, NP Caradonna, D Hallifax, E Turlizzi and JB Houston. (2012). Comparison of cryopreserved HepaRG cells with cryopreserved human hepatocytes for prediction of clearance for 26 drugs. Drug Metab Dispos, 40, 104-110. eScholarID:161179 | DOI:10.1124/dmd.111.042309

2011

  • 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

  • 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 Metabolism & Disposition, 38(12), 2139-2146. eScholarID:95973 | DOI:10.1124/dmd.110.035824

2009

  • Rowan A Stringer, Claire Strain-Damerell, Paul Nicklin, Houston JB. (2009). Evaluation of Recombinant Cytochrome P450 Enzymes as an in Vitro System for Metabolic Clearance Predictions. Drug Metabolism & Disposition, 37(5), 1025-1034. eScholarID:1d18770 | DOI:10.1124/dmd.108.024810

2008

  • Alison Parker, Houston J B. (2008). Rate-Limiting Steps in Hepatic Drug Clearance: Comparison of Hepatocellular Uptake and Metabolism with Microsomal Metabolism of Saquinavir, Nelfinavir, and Ritonavir. Drug Metabolism & Disposition, 36(7), 1375-1384. eScholarID:1d17250 | DOI:10.1124/dmd.108.020917

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