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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 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 Other drugs are prematurely withdrawn from the market due to toxicities arising from pharmacokinetic idiosyncrasies.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 hepatic 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 proteins). We are particularly interested in the the need to incorporate variability and uncertainty within the extrapolation process and transporter-mediated events in delineating hepatic clearance.

Molecular and kinetic basis of Drug-Drug Interactions
In the era of polypharmacy, drug-drug interactions (DDIs) 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 transporter proteins 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 enzyme induction effects due to drug treatment and chemical environmental exposure.

Research links

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 Manchester Pharmacy School. 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 Manchester Pharmacy School. This involves five faculty members and supports twenty research staff. As a consortium it operates in collaboration with, and financially supported by international pharmaceutical companies. All research is generic and involves the prediction of human pharmacokinetics.

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. 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.  He is a Fellow of the American Association of Pharmaceutical Scientists (AAPS) and received the International Society for Study of Xenobiotics (ISSX) 2014 European Scientific Achievement Award.

He has supervised over 60 graduate students.  His research publications in the area of drug metabolite kinetics in vivo and  in vitro exceed 200 and are highly cited.  He was named as a Thomson Reuters Highly Cited Researcher in 2015 - ranking among the top 1% most cited scientists in his subject field (Pharmacology & Toxicology) earning him the mark of exceptional impact. 

 

Qualifications

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

Collaborators and affiliated staff

CAPKR Collaboration

Leon Aarons

Aleksandra Galetin

Amin Rostami

Kayode Ogungbenro

Adam Darwch

Dave Hallifax

Postdoctoral Associate / PhD Students

Ayse Ufuk (Postdoctoral Associate)

Norikazu Matsunaga (Visiting Scientist)

James Harrison

Eva Sherbetjian

Shelby Barnett

Research Technican

Sue Murby

External Collaborators

John Miners

Simcyp Ltd

Selected publications

2015

  • Houston, J. B., Rowland, A., Hallifax, D., Nussio, M. R., Shapter, J. G., Mackenzie, P. I., ... Miners, J. O. (2015).

    Characterization of the comparative drug binding to intra- (liver fatty acid binding protein) and extra- (human serum albumin) cellular proteins. Xenobiotica, 45(10), 847-857. DOI:DOI:10.3109/00498254.2015.1021403. Publication link: 65713cde-93d5-46c7-9d4f-b801e411ea68
  • Houston, J. B., Ufuk, A., Somers, G., & Galetin, A. (2015).

    In Vitro Assessment of Uptake and Lysosomal Sequestration of Respiratory Drugs in Alveolar Macrophage Cell Line NR8383. Pharmaceutical Research, 32(12), 3937-3951. DOI:doi 10.1007/s11095-015. Publication link: 9d0e95d7-8ec9-4ff5-a462-c2513b4551d6
  • Houston, B., Assmus, F., & Galetin, A. (2015).

    In Silico Prediction of Hepatocellular Drug Binding. In host publication. (Vol. A10). Publication link: a9680c8c-7351-4499-86b0-e0b0527287db
  • Houston, B., Bruyn, T. D., Barton, H. A., Bi, Y-A., Cantrill, C., Galetin, A., ... Kosa, R. (2015).

    Cynomoglus monkey as a preclinical model for the investigation of hepatic uptake of OATP substrates. In host publication. (Vol. P11). Publication link: e60f29b5-66a0-424c-9592-052b7de5d61b
  • Houston, B., Kageyama, M., & Galetin, A. (2015).

    "Time dependent" inhibition of hepatic uptake transporters in hepatocytes and implications on the assessment of transporter-mediated drug-drug interactions. In host publication. (Vol. P43). Publication link: 17743e91-e910-41a5-a215-3152786b79df
  • Houston, B., Ufuk, A., Plumb, J., & Galetin, A. (2015).

    Comparison of respiratory drug accumulation and lysosomal sequestration in NR8383 and primary human al veolar macrophages. In host publication. (Vol. A11). Publication link: 11843377-cc0a-4770-b7a5-113fad0a27a9
  • Houston, B., Wood, F., & Hallifax, D. (2015).

    Assessing metabolic competence in isolated hepatocytes: Exploring the relationship between enzyme function and plasma membrane integrity via Saponin treatment. In host publication. (Vol. P10). Publication link: 23a552ec-b700-4463-862d-784dd5d64258

2014

  • Gertz, M., Tsamandouras, N., Säll, C., Houston, J. B., & 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. Pharmaceutical Research, 1-16. DOI:10.1007/s11095-014-1333-3. Publication link: eeb6ffa6-81fa-43a4-80fb-93a6de2f49f4
  • Nishimuta, H., Houston, J. B., & Galetin, A. (2014).

    Hepatic, intestinal, renal, and plasma hydrolysis of prodrugs in human, cynomolgus monkey, dog, and rat: Implications for in vitro-in vivo extrapolation of clearance of prodrugs. Drug Metabolism and Disposition, 42(9), 1522-1531. DOI:10.1124/dmd.114.057372. Publication link: bb0e366f-7e03-4967-8dca-e96db290d749
  • Smith, D., Artursson, P., Avdeef, A., Di, L., Ecker, G. F., Faller, B., ... Testa, B. (2014).

    Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition. Molecular Pharmaceutics, 11(6), 1727-1738. DOI:10.1021/mp400713v. Publication link: d24e8ca1-6f6b-4cb1-88cf-96e59b3b615c
  • Houston, J. B. (2014).

    Interplay between enzymes and transporters in defining hepatic drug clearance and intracellular concentration of drugs. Invited talk at The Royal Society of Chemistry, London, .. Publication link: a84640d5-c278-4838-9b5f-cfc537810b1f

2013

  • Gertz, M., Cartwright, C. M., Hobbs, M. J., Kenworthy, K. E., Rowland, M., Houston, J. B., & Galetin, A. (2013).

    Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: Application of PBPK Modeling in the assessment of drug-drug interaction potential. Pharmaceutical Research, 30(3), 761-780. DOI:10.1007/s11095-012-0918-y. Publication link: 0c4e5ddc-c32e-4320-9f8b-e6f238b26150
  • Gill, K. L., Gertz, M., Houston, J. B., & 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 Metabolism and Disposition, 41(4), 744-753. DOI:10.1124/dmd.112.050294. Publication link: 295aa66e-9b34-4d92-a8b4-d246bb89b232

2012

  • Burt, H. J., Pertinez, H., Säll, C., Collins, C., Hyland, R., Houston, J. B., & Galetin, A. (2012).

    Progress curve mechanistic modeling approach for assessing time-dependent inhibition of CYP3A4. Drug Metabolism and Disposition, 40(9), 1658-1667. DOI:10.1124/dmd.112.046078. Publication link: b1a7b05f-a557-435d-b4c6-9db3cdb47628
  • Jigorel, E., & Houston, J. B. (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. DOI:10.1124/dmd.112.045732. Publication link: 281514a9-0d00-4250-ad5b-798ed7aa3111
  • Ménochet, K., Kenworthy, K. E., Houston, J. B., & Galetin, A. (2012).

    Simultaneous assessment of uptake and metabolism in rat hepatocytes: A comprehensive mechanistic model. Journal of Pharmacology and Experimental Therapeutics, 341(1), 2-15. DOI:10.1124/jpet.111.187112. Publication link: 628790e4-e30a-44f6-8fb5-7b369a14bc3b

2011

  • Foster, J. A., Houston, J. B., & Hallifax, D. (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(2), 124-136. DOI:10.3109/00498254.2010.530700. Publication link: 52a71c50-3e8e-4ec2-8b8e-77fdedb90005
  • Yabe, Y., Galetin, A., & Houston, J. B. (2011).

    Kinetic characterization of rat hepatic uptake of 16 actively transported drugs. Drug Metabolism and Disposition, 39(10), 1808-1814. DOI:10.1124/dmd.111.040477. Publication link: 0fb8416f-d936-4356-8ebd-f7260bcd46e7

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