Volume 34
Issue 1, 2014
ISSX President’s Message By John O. Miners, ISSX President I would like to start my term as President of ISSX by acknowledging the role of members of Council who completed their terms in 2013: Bill Smith (President), Charles Crespi (Treasurer), and Councillors Brian Houston and Ikumi Tamai. On behalf of all ISSX members, I extend my thanks to Bill, Charles, Brian, and Ikumi for their enormous contributions to the Society. Bill’s commitment warrants special mention. Members may not be aware, but the road to ISSX Presidency can be long. Prior to becoming ISSX President, Bill served as Secretary-Elect for two years, Secretary for two years, and President-Elect for two years. Bill’s commitment is meritorious not just in terms of the time and effort he put into ISSX, but also for his vision as President in developing a strategic plan for the Society over the next three to five years and his engagement with other scientific groups, especially in Asia. As President, I will be supported by a strong leadership team over
the next two years—Geoff Tucker (President-Elect/Secretary), Andrew Parkinson (Treasurer), Jim Halpert (Treasurer-Elect), and Councillors Tom Baillie, Maria Almira Correia, Ann Daly, Richard Kim, Larry Marnett, Paul Ortiz de Montellano, Hiroshi Yamazaki, and Allan Rettie (Chair of the Scientific Affairs Committee). Council, and indeed the ISSX membership more broadly, is fortunate to be supported by ISSX Executive Director Steven Kemp and the staff in the ISSX Office (Zoë Fuller, Sarah Langan, and Kelly Marks). Over the next two years Council will be tasked with implementing key objectives from the strategic plan. These include increasing member value and participation, increasing internationalization, expanding scientific reach, improving operational excellence, and improving financial sustainability. With respect to the latter, ISSX achieved a surplus in 2013 thanks to the diligence of Council and the ISSX Staff. There was also substantial growth in
investments, further improving the financial position of ISSX. Two ISSX Scientific Meetings are scheduled for 2014, both of which will increase the international scope of the Society. The 5th AsiaPacific (AP) ISSX Meeting was held in Tianjin, China from May 9–12. The Meeting was hosted by the Chinese Society for the Study of Xenobiotics, our affiliate and partner in China. The venue for the Meeting was the attractive Binhai One Hot Spring Resort and the strong scientific program featured both regional and international speakers. Please join us for the joint 19th North American ISSX – 29th Japanese Society for the Study of Xenobiotics (JSSX) Meeting to be held in San Francisco from October 19–23. The program for the ISSX-JSSX Meeting will be released in the near future. Many members Continued on page 21
IN THIS ISSUE 1
ISSX President’s Message
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Book Review: Reactive Drug Metabolites
North American ISSX/ 3 19th 29th JSSX Meeting
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Welcome New Members
international ISSX 8 10th Meeting-Special Report
Book Review REACTIVE DRUG METABOLITES Editors: A. Kalgutkar, D. Dalvie, R. Obach, D. Smith John Wiley and Sons; Wiley-VCH Verlag GmbH & Co. KGaA. 402pp, ISBN 978-3-52733085-0, 2012
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This book contains a cornucopia of information, all to the better. Fifteen chapters, containing many subdivisions, cover various aspects of this absorbing topic. The sections are entitled, “Origin and Historical Perspective on Reactive Metabolites,” “Role of Reactive Metabolites in Genotoxicity,” “Bioactivation and Inactivation of Cytochrome P450 and Other Drug-Metabolizing Enzymes,” “Role of Reactive Metabolites in Drug-Induced Toxicity - The Tale of Acetaminophen, Halothane, Hydralazine, and Tienilic Acid,” “Pathways of Reactive Metabolite Formation with Toxicophores/ Structural Alerts,” “Intrinsically Electrophilic Compounds as a Liability in Drug Discovery,” “Role of Reactive Metabolites in Pharmacological Action,” “Retrospective Analysis of Structure-Toxicity Relationships of Drugs,” “Bioactivation and Natural Products,” “Experimental Approaches to Reactive Metabolite Detection,” “Case Studies on Eliminating/ Reducing Reactive Metabolite Formation in Drug Discovery,”
“Structural Alert and Reactive Metabolite Analysis for the Top 200 Drugs in the US Market by Prescription,” “Mitigating Toxicity Risks with Affinity Labeling Drug Candidates,” “Dealing with Reactive Metabolite - Positive Compounds in Drug Discovery,” and “Managing IADRs - a Risk-Benefit Analysis.” Following a historical overview of the emerging insights into drugrelated toxicity, the concept of the “toxicophore” is introduced; the appreciation that a particular chemical structure and molecular configuration may signal ensuing toxicity. Many deleterious compounds, although not initially toxic, have bolstered the understanding that as xenobiotics journey through the body the various enzymes they encounter may chemically alter their structures, yielding toxic metabolites. Structureactivity relationships are discussed as well as predictive strategies for toxicity assessment of reactive metabolite prone xenobiotics. Many of your favorites are included (e.g. aflatoxin, carbamates, cycasin, halothane, hydrazine, nitrosamines, thiophenes, vinyl halides) and these “usual suspects” are discussed in the light of current knowledge and accumulated wisdom. Many less well known candidates are also detailed.
This book is volume 55 in the “Methods and Principles in Medicinal Chemistry” series, initiated over 30 years ago by Wiley. It is comprehensive in its coverage and surprisingly straightforward to read, rendering sometimes difficult concepts painless. Well laid out, many lucid diagrams, pertinent references and a 9-page index with around 800 entries (estimated) add to its quality. This is an ideal book and companion on this fascinating subject.
Reviewed by
Steve Mitchell Faculty of Medicine Imperial College London London SW7 2AZ, UK
Book ordering information: John Wiley and Sons Corporate Headquarters 111 River Street Hoboken, NJ 07030-5774 United States of America Telephone: 201.748.6000 Facsimile: 201.748.6088 Email: info@wiley.com
The Atrium Southern Gate, Chichester West Sussex PO19 8SQ England Telephone: 44.1243.779777 Facsimile: 44.1243.775878 Email: customer@wiley.com
Upcoming Meetings 29th JSSX Meeting and 19th North American Meeting Hilton San Francisco, Union Square San Francisco, California, USA October 19–23, 2014
13th European Meeting University of Strathclyde Glasgow, Scotland, UK June 22–25, 2015
20th North American ISSX Meeting Hilton Orlando Bonnet Creek Orlando, Florida, USA October 17–21, 2015
Join ISSX and JSSX in San Francisco this October San Francisco is renowned for its steep rolling hills, eclectic architecture, and unique sights and sounds including the Golden Gate Bridge, cable cars, the famous Lombard Street, Alcatraz and much more. Its international airport is a major gateway to Asia with direct flights from more than 40 countries daily. We look forward to welcoming you to San Francisco in October for a socially rewarding and high-quality scientific meeting.
Present Your Work at the Meeting The International Society for the Study of Xenobiotics is pleased to co-organize a scientific meeting with the Japanese Society for the Study of Xenobiotics October 19–23, 2014 in San Francisco, CA. In 2005, ISSX partnered with JSSX and organized a highly regarded meeting in Maui, HI. Another joint meeting between our societies offers a wonderful opportunity to provide researchers both fundamental new findings and cuttingedge information related to xenobiotic metabolism and disposition and demonstrates our continued mutual support.
Why Submit an Abstract? •C ontribute your research to the leading international forum for scientists interested in the interactions of medicines and chemicals with living systems. • Provide attendees with the opportunity to learn about emerging fields and how they apply to DMPK. • Open dialogue among your peers to effectively develop strategies for active involvement in other areas of the science. • Gain recognition when your research is published in a special supplement of Drug Metabolism Reviews.
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The abstract submission deadline is Friday, June 27, 2014 at 11:59 p.m. Eastern Time (U.S.). Visit www.issx.org/ jssx-issx/abstracts to submit your abstract for the general or poster awards competition.
Issue 1, 2014
The meeting will begin on Sunday, October 19 with short courses on DDI prediction, metabolite biosynthesis and structure determination, Non-CYP metabolism, and a tutorial on using database mining to maximize the use of DMPK and DDI data during clinical development of new chemical entities. The short courses will be followed by a welcome reception for all attendees and registered guests. Fourteen scientific symposia encompassing a broad spectrum of topics important in the field will be featured as will plenary lectures by the ISSX North American Scientific Achievement Awardees and the JSSX Kitagawa and Young Investigator Awardees. In addition, there will be poster sessions, an exhibition hall, and multiple industrysponsored symposia.
We encourage all researchers involved in the investigation of drug metabolism, pharmacology, toxicology, molecular biology, and other related disciplines to submit an abstract for a poster presentation at the 19th North American ISSX/29th JSSX Meeting to be held in San Francisco, CA, USA October 19–23, 2014.
Lodging and Travel The Hilton San Francisco is the home of the 19th North American ISSX/29th JSSX Meeting. We have reserved a block of hotel rooms at a special rate for attendees of this meeting. Located approximately 14 miles from San Francisco International Airport (SFO) and Oakland International Airport (OAK), the hotel is easily accessible by airport shuttle, public transportation, taxi, and rental car.
San Francisco International Airport (SFO) offers nonstop flights to more than 74 cities in the US on 17 domestic airlines. Visit www.flysfo.com for up-to-the-minute departure and arrival information, airport maps, and details on ground transportation and more. Oakland International Airport (OAK) is served by most major US carriers, with more than 150 daily departures. The site www.oaklandairport.com provides details about ground transportation from Oakland International Airport. Depending on the agreements between the United States and your country, a visa may be required. Please check with your local embassy/consulate or travel agent to obtain information regarding visa requirements. To request a Letter of Invitation from JSSX/ISSX to help facilitate visa arrangements, please view the visa information page on the JSSX/ISSX web site at www.issx.org/visa.
North American Meeting Awards Hilton San Francisco Union Square Hotel 333 O’Farrell Street San Francisco, California 94102 USA Telephone: + 1(415) 771-1400 The meeting web site, www.issx.org/jssx-issx/hotel includes a link where attendees can access the JSSX / ISSX hotel accommodations reservations page to conveniently secure hotel accommodations at our group rate online. Alternatively, you may telephone the Central Reservations department at: +1 (855) 786-4701. The city of San Francisco is served by two major airports, an extensive public transportation system, and many private taxi, ferry, and shuttle services. For a complete list of transportation options in and around San Francisco, be sure to visit the meeting web site.
ISSX established its awards program to recognize scientific achievements of the Society’s members. Receiving an ISSX award is a prestigious honor. Consider submitting a nomination of a worthy colleague or peer. Nominations are being accepted online at www.issx.org/awards/ nominations for the following ISSX awards to be presented at the meeting in San Francisco: North American Scientific Achievement Award Presented to an ISSX member who has made major scientific contributions to the field within the North American region. The purpose of this award is to recognize meritorious contributions by senior or mid-career scientists that have had a major impact on research in the field. The North American Scientific Achievement Award is named in Honor of Ronald W. Estabrook and is sponsored by XenoTech.
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Submit an abstract for the JSSX / ISSX Meeting in San Francisco, USA October 19–23, 2014. Visit www.issx.org/jssx-issx/abstracts to submit an abstract. Abstract submissions for the general poster presentations and Poster Awards Competition are due by Friday, June 27, 2014.
North American New Investigator Award - Presented to an ISSX member who has made significant contributions to the field during their early career years (normally within 5–10 years from the time of receiving his/her highest earned degree). The purpose of these awards is to encourage and recognize developing scientists who are active in the field within the North American region. The process is simple and there are few materials to assemble. Please provide the following:
candidate’s nomination, (The maximum length of each letter should not exceed two pages.) • A summary detailing the relevant achievements of the candidate, (The maximum is 2–3 pages.) • A curriculum vitae and a bibliography (note bibliography and not biography) of the candidate, and • A high resolution headshot photograph (color preferred) in .jpg format. The nomination submission deadline is Tuesday, July 1, 2014. Please consider participating by submitting a nomination and providing a deserving candidate a very special honor.
•A letter written by the nominator which outlines the reason why they believe the nominee should receive the award, • No less than two and no more than four supporting letters from others presenting the case for the
Register today at www.issx.org/jssx-issx/registration.
Sunday, October 19 • Short Course Registration Fees: Category: Early Regular On-Site (Feb. 1 - June 30) (July 1 - Oct. 10) (After Oct. 10) ISSX or JSSX Member $175 $225 $250 Student/Postdoc Member $100 $125 $150 Nonmember $225 $275 $325 Meeting Registration Fees: Category: Early Regular On-Site (Feb. 1 - June 30) (July 1 - Oct. 10) (After Oct. 10) ISSX or JSSX Member $615 $715 $795 Student/Postdoc Member $250 $275 $300 Nonmember $745 $845 $945
Meeting Organizing Committee Bill Smith, PhD, Pfizer Inc., La Jolla Labs Hiroshi Suzuki, PhD, The University of Tokyo Hospital Peter W. Swaan, PhD, University of Maryland Mikihisa Takano, PhD, Hiroshima University Ikumi Tamai, PhD, Kanazawa University Toshio Teramura, PhD, Astellas Pharma, Inc. Hiroshi Yamazaki, PhD, Showa Pharmaceutical University Xiao-bo Zhong, PhD, University of Connecticut School of Pharmacy
ISSX Members receive a substantial discount on registration fees. Join ISSX or renew your membership today. www.issx.org
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ISSX 2014 Membership
Issue 1, 2014
Eric Johnson, PhD, (Meeting Co-Chair The Scripps Research Institute Tetsuya Terasaki, PhD, (Meeting Co-Chair) Tohoku University Kan Chiba, PhD, Chiba University Frank Gonzalez, PhD, National Cancer Institute Natilie Hosea, PhD, Pfizer Inc. Takashi Izumi, PhD, Daiichi Sankyo Co., Ltd. Paul Ortiz de Montellano, PhD, University of California, San Francisco R. Scott Obach, PhD, Pfizer Inc.
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ISSX Welcomes New 2014 Members! Sunjoo Ahn, Korea Research Institute of Chemical Technology, Korea Ahmed Almousa, University of Saskatchewan, Canada Ahmet Altay, METU, Turkey Shinsuke Aoyama, Sekisui Medical Co., Ltd., Japan Rachel Basile, Rigel, Inc., United States Bruno Bournique, Inventiva, France Jiaojiao Cao, Shen Yang Pharmaceutical University, China Perry Cao, Alkermes, United States Hea-Young Cho, CHA University, Korea Yunhai Cui, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany Tuba Culcu, Middle East Technical University, Turkey Debarun Das, CFD Research Corporation, United States David Evans, Johnson & Johnson, United States Hong Gao, Vertex Pharmaceuticals, United States Yangyang Gao, Sichuan University, China C. Edwin Garner, Oso Corredor Scientific Consulting, United States Wandee Gritsanapan, Mahidol University, Thailand Jian Guo, AstraZeneca Pharmaceuticals LLP, United States Miao Hu, The Chinese University of Hong Kong, Hong Kong Lin Ji, Shen Yang Pharmaceutical University, China E.P Keshawa, IBMBB, University of Colombo, Sri Lanka Hyojin Kim, INJE University, Korea Jerome Lasker, CYP450-GP, United States Jong-Hwa Lee, Korea Chunyan Li, Shen Yang Pharmaceutical University, China Jia-Jun Li, Suzhou University, China Jie Li, China Jinglai Li, Beijing Institute of Pharmacology and Toxicology, China Min Li, Beijing Hospital, China Shao-Rong Li, AstraZeneca Global R&D, China Wei Li, College of Medicine, Yangzhou University, China Weiwei Li, Shen Yang Pharmaceutical University, China Yemeng Li, China Qiongfeng Liao, Guangzhou University of Chinese Medicine, China Dongju Lin, Shen Yang Pharmaceutical University, China Manna Lin, China Weiyi Liu, Kanazawa University, Japan
Dan Lu, Shen Yang Pharmaceutical University, China Rong Lu, Tianjin Institute of Pharmaceutical Research, China Iain Martin, Merck & Co., United States Anuka Mendis, Sri Lanka Ricard Mis, FAES FARMA, Spain Yi Yun Pang, National University of Singapore, Singapore Ying Peng, Shen Yang Pharmaceutical University, China Hui-Xin Qi, Suzhou University, China Wen-Yuan Qi, Beijing Hospital, China Solomon Rotimi, Covenant University, Nigeria Heonmin Ryu, China Ursula Schumacher, EUROFINS, China Mahadevabharath Somayaji, CFD Research Corporation, United States Murali Subramanian, Syngene International, India Yao Tang, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, China Adrian Vazquez, Biosurplus, United States Lei Wang, Harbin Engineering University, China Mei-Yu Wang, Suzhou University, China Ye-Dong Wang, Suzhou University, China Yu-Ya Wang, AstraZeneca Global R&D, China Zhijun Wang, Western University of Health Sciences, United States De-Duo Xu, RILD Research Institute for Liver Diseases, China Wei Xue, Beijing Hospital, China Jocelyn Yabut, Merck & Co., United States Bei Yan, Beijing Hospital, China Yu-Mei Yan, AstraZeneca Global R&D, China Jia Yu, Shen Yang Pharmaceutical University, China Jin-Qiang Zhang, AstraZeneca Global R&D, China Tianhong Zhang, Institute of Pharmacology and Toxicology, China Yifan Zhang, China Zhoupeng Zhang, Merck Co., Inc., United States Liwei Zheng, Shen Yang Pharmaceutical University, China Tianyan Zhou, Peking University, China Conghui Zhu, Research center for EcoEnvironmental Science, CAS, China
ISSX members have access to a variety of exclusive benefits including: A Subscription to the ISSX Newsletter -‐ Members receive a quarterly newsletter that highlights Society news, member spotlights, upcoming meetings, late breaking scientific news, and much more. Reduced Registration Fees -‐ Members receive significant discounts on registration fees for all ISSX meetings and workshops. Recorded Educational Content -‐ New in 2014 -‐ Members can access recorded content online at a reduced members-‐only rate. Abstract Presentations -‐ Members have the opportunity to submit abstracts to present their work with other leaders in the field at ISSX meetings. Searchable Meeting Abstracts -‐ Members may perform searches for and cite abstracts from past ISSX meetings. Networking Opportunities -‐ Meet with other local and international leaders interested in DMPK. Society Awards Program -‐ Only ISSX members are eligible for the prestigious Scientific Achievement Awards presented at our regional meetings. Travel Grants -‐ Eligible members may apply for travel assistance to attend ISSX regional and international meetings. Membership Directory -‐ Our searchable online membership directory makes connecting with fellow researchers convenient. Special Journal Subscription Discounts -‐ Members receive special subscription discounts to multiple scientific journals, including Drug Metabolism Reviews, Annual Review of Pharmacology and Toxicology, and many more. Hold Office and Serve on a Committee -‐ Holding a position of leadership in ISSX is a tremendous opportunity to serve your peers worldwide, to develop important skills, help set the work plan of a prestigious international scientific society, and be recognized as a leader volunteer of an international scientific society. Vote in ISSX Elections -‐ Helping to choose the future leaders of ISSX sets the path of our organization and provides you the opportunity to elect those who best represent your interests. Most of all, your membership indicates your support of our mission to advance the understanding of the interactions of medicines and chemicals with living systems and helps sustain our program of operations. Please support ISSX by renewing your membership today!
www.issx.org/membership/renew
International Toronto, Ontario, Canada • September 29 - October 3, 2013
The 10th International ISSX Meeting was held at the Westin Harbour Castle hotel in Toronto, Ontario, Canada September 29–October 3, 2013. This meeting, chaired by Denis Grant of the University of Toronto, brought together 940 speakers, participants, and exhibitors representing 35 nations.
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The meeting was preceded by four short courses attended by 281 meeting registrants. The courses featured a range of topics: Metabolomic Profiling as a Tool for Identifying Novel Drug-Target Reactions; Model Systems and Methods for Assessing Uptake and Efflux of Small Molecules; Strategies and Techniques for Predicting Human Drug Metabolism and Drug-Drug Interactions; and Application of Novel Mass Spectrometric Methods to Drug Metabolism and Pharmacokinetics Studies.
Special Report
The scientific program included lectures on a variety of innovative and informative topics that were delivered in parallel symposia and plenary sessions. Learn more about the subject matter presented in the session summary section of this report. The meeting included an optional tour and reception at the Hockey Hall of Fame. Participants enjoyed an opportunity to pose with the Stanley Cup, learn about the history of hockey, and practice shots in the rink. The Society is grateful to the Meeting Chair and Meeting Organizing Committee as well as all of the session chairs and speakers. The poster presenters, attendees, and exhibiting companies all contributed to the great success of this meeting and their participation and support is greatly appreciated.
The meeting program commenced with a keynote session, Systems Pharmacology-Systems Biology meets Drug Discovery & Development, presented by Douglas Lauffenburger of the Department of Biological Engineering, MIT, in Cambridge, Massachusetts, USA. The keynote was followed by the presentation of the colors by Constable Terry Russel of the Royal Canadian Mounted Police. Following the presentation, two members of the 48th Highlanders of Canada Pipes and Drums played the bagpipes as they led attendees to the welcome reception in the exhibit hall where attendees could meet with fellow attendees, and spend time with the 51 companies exhibiting their products and services at the meeting.
Meeting Organizing Committee:
The meeting also featured the presentation of the prestigious ISSX Awards. The 2013 Frederick J. Di Carlo Award was presented to Bob Hanzlik, Ph.D. The R.T. Williams Distinguished Scientific Achievement Award, sponsored by Charles Crespi and Family, was presented to Yuichi Sugiyama, Ph.D. Both awardees were presented with an honorarium and medal and each presented a lecture to the award session attendees.
Tom Massey, Queen’s University, Kingston, ON, Canada
Denis Grant (Meeting Chair), University of Toronto, Toronto, ON, Canada Stelvio Bandiera, University of British Columbia, Vancouver, BC, Canada Jack Bend, University of Western Ontario, London, ON, Canada Chantal Guillemette, Laval University, Quebec, QC, Canada Malle Jurima-Romet, Celerion, Montreal, QC, Canada David K.H. Lee, InterVivo Solutions, Inc., Mississauga, ON, Canada Eddie Morgan, Emory University, Atlanta, GA, USA Sandy Pang, University of Toronto, Toronto, ON, Canada Allan Rettie (SAC Member), University of Washington, Seattle, WA, USA David Riddick, University of Toronto, Toronto, ON, Canada Continued on next page
Nathalie Rioux, Epizyme, Cambridge, MA, USA Rachel Tyndale, University of Toronto, Toronto, ON, Canada Peter Wells, University of Toronto, Toronto, ON, Canada Short Course, Speaker, and Poster Presentation Abstracts are available at www.issx.org/abstractdatabase.
The 2013 Frederick J. Di Carlo Distinguished Service Award honors an ISSX member from any region with an illustrious record of important service to the Society and its goals. The 2013 recipient is Robert P. Hanzlik, Ph.D., of the University of Kansas. Also a past president of ISSX, Professor Hanzlik was selected to receive this honor to recognize and
ISSX Honors Distinguished Scientists for Scientific Achievements and Service A highlight at the 10th International ISSX meeting was the presentation of the R.T. Williams Distinguished Scientific Achievement Award and the Frederick J. Di Carlo Distinguished Service Award. These are the Society’s most prestigious awards and they are only bestowed every three years to outstanding individuals. Generously sponsored by Charles Crespi and Family, the R.T. Williams Distinguished Scientific Achievement Award honors an ISSX member or non-member from any region who has made substantial and seminal scientific contributions to the field over a sustained period. The focus of this award is the individual’s scientific accomplishments and it is intended to recognize the best in the field internationally. Professor Yuichi Sugiyama, a world leader in drug transporters and physiologically-based pharmacokinetics, was presented this award at the Society Awards Ceremony on September 30 in Toronto, Canada. A past president of both ISSX and JSSX, Professor Sugiyama, Ph.D., currently conducts his research at the RIKEN Innovation Center, Research Cluster for Innovation, Saitama, Japan.
ISSX President-Elect/Secretary John Miners presents the Frederick J. Di Carlo Award to recipient Bob Hanzlik.
ISSX President-Elect/Secretary John Miners and Charles Crespi present the R.T. Williams Award to recipient Yuichi Sugiyama.
Issue 1, 2014 Meeting Chair, Denis Grant, receives a gift from ISSX President, Bill Smith.
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Left to right: ISSX President Bill Smith, R.T. Williams Award recipient Yuichi Sugiyama, Frederick J. Di Carlo Award recipient Bob Hanzlik, ISSX President-Elect/Secretary John Miners, 10th International Meeting Chairman Denis Grant.
Attendees and exhibitors enjoy the Opening Welcome Reception.
celebrate his history of devoted service to ISSX and its goals. Professor Hanzlik is a distinguished scientist with an international reputation and has served in a variety of volunteer leadership positions for ISSX.
and discussed several recent developments relating to nuclear receptors as regulators of xenobiotic and central endogenous metabolism as well as potential and problems of these proteins as novel therapeutic targets.
The Awards Ceremony was marked by the presentation of gold medals of honor to both Professor Sugiyama and Professor Hanzlik.
Pharmacogenomics and Personalized Medicine: Progress in Clinical Implementation
Parallel Sessions
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Nuclear Receptors as Regulators of Drug Metabolism and as Therapeutic Targets The session was co-chaired by Dr. Uli Zanger (Bosch Institute of Clinical Pharmacology) and Dr. Hongbing Wang (University of Maryland School of Pharmacy). Several ligand-dependent nuclear receptors not only orchestrate the regulation of ADME gene batteries in response to xenobiotic challenge, but also have important functions in physiological processes, making them attractive drug targets. As pointed out by Dr. Jason Matthews (University of Toronto), the regulation of nuclear receptor function by ADP-ribosylation exemplified by the TiPARP/ARTD14 mono-ADPribosyltransferase may represent new opportunities for therapeutic intervention. Hongbing Wang showed how selective human CAR activators can be used as novel components for combined treatments of hematopoietic malignancies. Dr. Wen Xie (University of Pittsburgh) focused on xenobiotic receptors PXR and CAR in endobiotic functions of energy metabolism and the functional crosstalk to drug metabolism, as well as their use as potential therapeutic targets to manage metabolic diseases. Finally, Dr. Uli Zanger outlined the newly discovered, human-specific, role of PPARalpha as inducible regulator of drug metabolizing CYP450s and other ADME genes, and how this relates to its function as master regulator of lipid homeostasis and to its renewed interest as drugs and nutraceutical targets. Taken together, the well-attended session presented
This session was chaired by Dr. Rachel Tyndale (CAMH and University of Toronto). Speakers were Dr. Munir Pirmohamed (University of Liverpool), Dr. James M. Hoffman (St. Jude Children’s Research Hospital), Dr. Larisa H. Cavallari (University of Illinois at Chicago), and Dr. Dan M. Roden (Vanderbilt University School of Medicine). Patients display substantial variability in the extent of benefit and in adverse drug reactions; some of this is due to pharmacogenomic variation. Although many drug-phenotype associations have been described, few have been incorporated into clinical practice. While barriers remain, many that have been addressed and overcome included selecting patients for genotyping because they are at risk for receiving target drugs, engaging the practitioner community, identifying actionable drug-gene pairs, deploying genotyping in a CLIA environment, and developing and deploying clinical decision support. In the past, there was a lack of freely available, peer-reviewed, updatable, and detailed gene/drug clinical practice guidelines, but now the Clinical Pharmacogenetics Implementation Consortium (CPIC), a shared project of PharmGKB and the Pharmacogenomics Research Network (PGRN), provides guidelines that enable the translation of genetic laboratory test results into specific prescribing decisions for patients. Computational tools, such as clinical decision support (CDS) delivered through an electronic health record (EHR) is essential to facilitate gene-based drug prescribing. Active CDS that provides concise gene-based drug prescribing recommendations at the time an affected drug is ordered is particularly important because pharmacogenetic tests can be conducted preemptively and have lifetime implications. Multiple centers are adopting these programs which Continued on next page
will allow accrual of sufficiently large patient subsets to begin to assess impact on healthcare outcomes. Regulation of Drug Transporter Expression and Function The regulation of drug transporter expression and function symposium consolidated speakers from industry, academia, and government to provide an overview on the importance of drug uptake and efflux transporters in drug disposition and how these are regulated in health and disease. Dr. Joseph Ware (Genentech) discussed the need to consider potential interaction with transporters during the process of drug discovery and development. He highlighted recent recommendations of the second International Transporter Consortium workshop. Dr. Curtis Klassen (University of Kansas Medical Center) described the transcriptional activation of drug uptake and efflux transporters by critical xenobiotic-sensing nuclear receptors. He included recent work demonstrating novel PXR-DNA binding sites and patterns to transporter genes in mouse liver. Dr. David Miller (NIH/NIEHS) reviewed the important protective role of the ABC efflux transporters at the blood-brain and bloodspinal cord barriers. He reviewed recent studies which have identified numerous and diverse transcriptional factors that regulate the ABC efflux transporters at CNS barriers. Dr. Micheline Piquette-Miller (University of Toronto) presented research findings which demonstrate an inflammation-mediated downregulation in the expression and activity of many uptake and efflux transporters in animal models of protozoal, bacterial and viral infection. Results from current studies in human tissues which indicate comparable disease or inflammation-mediated changes were also discussed. Application of Structural Biology to the Prediction of Drug Response, Metabolism and Toxicity
Cell Type Specific Mechanisms of Adverse Drug Reactions
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Dr. Michael Aleo (Pfizer, Drug Safety Research and Development) opened the session in front of approximately 300 attendees and gave an introductory overview entitled “In vitro Approaches to Detect Drug Induced Organ Toxicities: Learnings and Future Perspective” presenting approaches and challenges in mounting large screening campaigns to detect specific and broad drug-induced organ injury to ultimately influence the selection of a prioritized list of small molecules for more advanced studies using the Pfizer experience as a model. This was followed by a presentation by Dr. Jack Uetrecht (University of Toronto) on “Reactive Metabolite Formation in the Skin and the Mechanism by which it Causes a Skin Rash.” Dr. Uetrecht provided strong evidence that covalent binding of nevirapine in the skin is due to metabolite formation and covalent binding of a benzylic sulfate of 12-OHnevirapine. Although the sulfate can be made by the liver the presence of a sulfotransferase in skin appears to be more important in mediating the local skin effect where this metabolite activates inflammasomes in keratinocytes. Dr Larry Lash (Wayne State University School of Medicine, Department of Pharmacology) spoke next on the “Role of Species- and Cell Type-Specific Expression of Membrane Transporters in Nephrotoxicity.” Dr. Lash showed that renal cortical mitochondria are more susceptible to chemical-induced injury and that overexpression of two mitochondrial anion transporters, the dicarboxylate (DIC, Slc25a10) and oxoglutarate (OGC, Slc25a11) carriers, in NRK-52E cells resulted in increased mitochondrial uptake of glutathione (GSH) and protection from chemically induced apoptosis. In a diabetic model of nephropathy he also showed that despite higher cytosolic and mitochondrial GSH content and rates of GSH transport into mitochondria were only partially due to changes in expression of mitochondrial GSH carriers and were mostly due to higher substrate supply. There was an increase in sensitivity to apoptosis of renal proximal tubule cells in the diabetic state as well. Dr. Pollen Yeung (Dalhousie University, College of Pharmacy) presented interesting work on “ATP Metabolism in RBC as in vivo Biomarker for Cardiovascular Toxicity.” Dr. Yeung demonstrated a post-exercise effect on red blood cell (RBC) intracellular ATP and GTP content, where differences were positively correlated to the differences in post-exercise
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Dr. Jim Halpert from UC San Diego chaired this parallel session. The rationale in selecting speakers was to feature both Phase I and Phase II enzymes and to incorporate computational as well as structural approaches. The session was kicked off by Dr. Eric Johnson (Scripps Research Institute) who presented his recent work on “Structural Determinants of P450 Metabolism: A Moving Target.” The main theme was recent breakthroughs in facile crystallization of CYP2D6 complexes, which now allow structures to be solved rapidly enough to aid drug discovery projects. Next, Dr. Edith Sim (University of Oxford and Kingston University) presented recent studies of “Arylamine N-Acetyltransferases Structure in Drug Metabolism and Drug Discovery.” The most recently solved NAT structure, that from Mycobacterium tuberculosis, can inform design of inhibitors of this target for anti-tubercular therapy. Dr. Hao Sun (Pfizer) then presented his work on “Using Crystal Structures of Drug Metabolizing Enzymes in Mechanism-Based Modeling for Drug Design.” He showed clearly how
the availability of multiple crystal structures of a single enzyme, such as CYP3A4, can guide medicinal chemists in overcoming metabolic liabilities of lead compounds. Finally, Dr. Jim Halpert presented his work on CYP2B enzymes, posing the question “Can We Understand and Predict Ligand Binding to a Highly Flexible P450?” Jim’s recent work has shown that a relatively small number of structures can explain the binding of most high affinity ligands of CYP2B4 and 2B6. Overall, the session was well attended and received.
hemodynamic effects between normal and spontaneously hypertensive rats. Lastly, Dr. Tracy Marion, (Qualyst Transporter Solutions) spoke on “Towards a More Predictive Model: Effect of Telmisartan on Taurocholate Disposition in B-CLEAR® Cryopreserved Sandwich-Cultured Hepatocytes Compared to BSEPExpressing Membrane Vesicles.” This talk focused on the need to measure intracellular, not extracellular levels of drug to truly understand transporter driven effects using sandwich cultures of hepatocytes, especially in relation to interpreting isolated vesicle information for a specific transporter such as bile salt export protein (BSEP). Use of PBPK Modeling in Pharmaceutical Safety Assessment This session focused on the application of physiologically-based pharmacokinetic (PBPK) modelling approaches in drug safety assessment. In addition to three experts in the area, speakers Dr. Aleksandra Galetin (University of Manchester), Dr. Harvey Clewell (The Hamner Institutes for Health Sciences) and Dr. Ursula Gundert-Remy (Drug Commission of the German Medical Association), the session also provided an excellent opportunity to the young researchers on the pre- and postdoctoral level Ayse Ufuk (University of Manchester) and Evita van de Steeg (TNO) to present their posters. Talks provided a number of examples to illustrate the integration of the in vitro transporter kinetic parameters generated in different cellular systems in PBPK models in order to simulate tissue exposure, assess drug safety or drug-drug interaction risk. Additionally, the application of physiologically-based toxicokinetic modelling as a risk assessment tool across different populations and for improved understanding of liver toxicity was demonstrated. The session also illustrated in vitro and in silico approaches to investigate lysosomal trapping in alveolar macrophages and its role in safety and efficacy of inhaled molecules.
on the application of the guideline over the first 6 months of use. Dr. Thomayant Prueksaritanont (Merck) shared an industry perspective using case studies to highlight potential complications and key recent learnings in the investigation of transporter-mediated DDIs and DDIs related to metabolites. The “MIST” guidances emphasized the importance of human radiochemical excretion and metabolism studies. However, new technologies such as high resolution LC-MS/MS have taken hold in the 5 years since the guidances were issued. Dr. Greg Slatter’s talk explored the past, present, and future of how human metabolism is done during clinical development.
The session was organized by the ISSX Committee on Regulatory Affairs (CORA) and by the Session Chair, Dr. Greg Slatter (Amgen, Inc.). Three presentations considered the recent FDA and EMA DDI guidance/ guidelines. The last session considered changes in the investigation of human in vivo metabolism over the last 5 years. The presentation by Dr. Lei Zhang (FDA, CDER) provided an overview on key elements in the FDA’s draft drug interaction guidance including regulatory science considerations and new science that can guide the evaluation of drug–drug interactions during the drug development process. The European Drug Interaction guideline has gone through a major revision. Dr. Eva Gil Berglund’s (Medical Products Agency) presentation addressed the most important updates and reflections
Toxicogenomic and Metabolic Profiling: Current Status and Future Utility in Assessing Drug Efficacy and Safety The application of toxicogenomic and metabolomic profiling in assessing chemical and drug safety was described in five complementary presentations. The presentation by Session Chair Dr. Tim Zacharewski (Michigan State University) integrated genome-wide ChIP-chip, gene expression and hepatic metabolome data with histopathology to further elucidate the aryl hydrocarbon receptor (AhR)-mediated progression of steatosis to steatohepatitis with fibrosis in 2,3,7,8-tetrachlrorodibenzo-p-dioxin treated mice. Dr. Rima Kaddurah-Daouk (Duke University Medical
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Regulatory Perspectives in Drug-Drug Interactions and Metabolites in Safety Testing
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from the tissues after drug candidate application. All four lectures could delineate quite high efficiency of the molecular imaging in tissue and whole-body level for drug development of course for humans. Development and Uses of Hepatocyte-Derived and Hepatocyte-Like Cells for Predicting Human Drug Metabolism
School) described the new discipline of pharmacometabolomics that captures environmental and microbiome influences on drug response and individual variation. Two studies were presented by Dr. Lining Guo (Metabolon, Durham, NC) using an unbiased global metabolomics platform to investigate the testicular toxicity of ethylene glycol monoethyl (EGME), and the elicited metabolomic profile of 13 hepatotoxicants to gain insights into drug-induced liver injury (DILI). In addition, two abstracts were selected for platform presentations. Guillaume Margaillan (Laval University) used targeted quantitative proteomics to further elucidate the variability of the glucuronidation pathways. The last speaker, Dr. Robin Haw (Ontario Institute for Cancer Research), described the development and use of the Reactome Knowledgebase, an open access, open-source, manually curated, peer-reviewed computational platform for pathway and network analysis. Each presentation clearly demonstrated the potential of these emerging technologies in chemical and drug safety but also described the challenges of associating toxicogenomic and metabolomic profiles to mechanisms of toxicity. Tissue Imaging and Distribution Studies in Drug Development
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The aim of this symposium was to demonstrate the recent progress in molecular imaging technologies in tissue- and whole body-level of drug disposition quantitatively. The first three lectures by Session Chair, Dr. Yasuyoshi Watanabe (RIKEN), Dr. Tomotaka Shingaki (RIKEN), and Dr. Tetsuya Suhara (NIRS) were mostly focusing on the Positron Emission Tomography (PET) studies on evaluation of drug candidates’ efficacy, pharmacokinetics, and dose determination in humans including healthy volunteers and patients, and normal, gene-manipulated, and disease-model animals. PET is quite successful not only in clinical diagnosis, but also in drug development, since PET could apply to functioning human with very high sensitivity (so highly safe), specificity, and reliable quantification in functionality. The lecture by Dr. Stephen Castellino (GlaxoSmithKline) showed a beautiful contribution by Maldi-imaging MS method for frozen sections
The promises of stem cell technology for applications in regenerative medicine and drug discovery rely on its ability to provide a source of human cells that accurately reflect the hepatocyte in vivo phenotype, stably maintain this phenotype in culture, and can be provided in large scale and at a reasonable cost. Dr. Nicholas RF Hannan (Laboratory for Regenerative Medicine, University of Cambridge) presented a simple defined culture system to derive and expand human foregut stem cells from human pluripotent stem cells, providing a unique in vitro model of human development and a convenient source for cell based therapy. He showed that culture of hepatocyte-like cells in clumps and in a threedimensional (3D) condition improves the maturation and the stability of the hepatic phenotype. Moreover, reprogramming mature differentiated cells into induced pluripotent stem cells (hiPSC) can be used to model inherited metabolic disorders. Dr. Petter BjÜrquist (Cellectis AB) demonstrated how a panel of human embryonic stem cells (hESC) and hiPSC lines generated from healthy donors, can be expanded using a novel highly efficient culturing system to provide sufficient cell material for further differentiation and toxicity studies. Robust differentiation protocols were applied that allowed a large scale and industrial production of hepatocyte-like cells from any iPS cell lines with individual cytochrome P450 activities, reflecting general population variation. Dr. Hiroyuki Mizuguchi (Graduate School of Pharmaceutical Sciences, Osaka University) reported the optimization of the differentiation and function of hepatocyte-like cells generated from hESC by a method that employs stage-specific transient overexpression of hepatocyte-related transcription factors and 3D spheroid culture systems. Cells might be used to predict metabolism-mediated toxicity. He also established long-term culture conditions of selfrenewing hepatoblast-like cells from hESCs and hiPSCs that would lead to a stable supply of hepatocyte-like cells for medical application such as drug screening and liver cell transplantation. Session Chair, Dr. Martine Daujat-Chavanieu’s presentation (Inserm U1040, Montpellier) addressed the effects of an environmental chemical described as etiologic agents of HCC on the behavior of hepatic progenitor cells isolated from the non-parenchymal fraction of human liver. Continuous exposure to dioxin inhibited their differentiation while it stimulated their proliferation. Sustained activation of the Ah Receptor resulted in an inflammatory response and chemokines secretion that could be part of the mode of action of dioxin as a tumor promoter.
Plenary Sessions
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Drug Metabolizing Enzymes as Potential Therapeutic Targets Talks in this plenary session focused on both phase I and phase II enzymes. Dr. Emily Scott (University of Kansas) presented “Inhibition of cytochrome P450 17A1: Targeting androgen production in prostate cancer,” revealing that 17A1-targeted prostate cancer drugs in use and development bind multiple steroidogenic P450 enzymes, a potential source of side effects. Information was presented on structural features of 17A1 and small molecules that might enable better selectivity, as explored through iterative analog design, testing, and new X-ray structures with 17A1. Dr. Rod Minchin (University of Queensland) presented “Targeting the arylamine N-acetyltransferases in cancer.” Within the arylamine N-acetyltransferases catalyzing acetylation of aromatic and heterocyclic amines, the human NAT1 isozyme is a biomarker for luminal breast cancer. NAT1 overexpression confers growth advantage and chemo-resistance in some cancer cells. NAT1 inhibition with small molecules or siRNA leads to reduced growth and invasion plus changes in major metabolic pathways important in tumor cells. This suggests NAT1 as a novel drug target for cancer and other proliferative diseases. The third speaker, Dr. Rheem Totah (University of Washington), discussed the emerging role of CYP2J2 in drug metabolism and its potential as a chemotherapeutic target. Dr. Totah stressed the importance of CYP2J2 in maintaining the cardiomyocyte and presented data demonstrating that inhibition of CYP2J2 and EET reduction in cardiac tissue is a potential mechanism for many cardiotoxic drugs. Utility of Genetic and Epigenetic Technologies in Drug Development and Safety Assessment This session was chaired by Dr. Ann Daly (Newcastle University). The objective was to explain how recent advances in genomics, including the use of genome-wide association studies and next generation sequencing, have impacted on the drug development process and
on understanding individual suspectibility to serious adverse drug reactions, together with the underlying mechanisms. The first speaker, Dr. Tom Urban (Duke University), provided an excellent introduction to the use of next generation sequencing to perform exome and whole genome sequencing, including costs. Dr. Urban described how exome sequencing is being used widely and successfully to identify causative mutations in Mendelian genetic diseases and more limited success up to now in applying it to the study of serious adverse drug reactions including QT prolongation, isoniazid-induced liver injury and aplastic anemia following interferon treatment. Dr. Philippe Sanseau (GSK) then described the application of genetic data to repositioning drugs. Many of the recently reported genes that are risk factors for common diseases are already targeted by drugs on the market or in development. However, for over 90 of these drugs, the indication for which the drug was developed is different to the disease to which the gene has been shown to contribute. Evaluating these drugs as treatments for different diseases can therefore be valuable. Finally, Dr. YT Chen (Academia Sinica) discussed immunogenetic risk factors for adverse drug reactions affecting the skin. He discussed genetic data on HLA alleles as risk factors and an additional contribution from a specific clonotype of the T cell receptor. The underlying mechanism by which Stevens-Johnson syndrome and related skin reactions develop involves production of high levels of cytotoxic secreted granulysin by immune cells causing keratinocyte death. Identification and Use of Novel Biomarkers for Xenobiotic-Induced Toxicity Biomarkers can be useful indicators of normal biological processes, pathogenic processes, or responses to a therapeutic intervention. This plenary session focused on the identification and use of novel biomarkers for xenobiotic-induced toxicity. Dr. Kevin Park (MRC Centre for Drug Safety Science at the University of Liverpool) discussed mechanistic biomarkers of drug-induced liver and kidney injury. Current biomarkers often lack sensitivity and/or specificity and may only relate indirectly to toxicity mechanisms. Continued on next page
New investigational biomarkers for acetaminophen hepatotoxicity and aminoglycoside nephrotoxicity were outlined, with discussion of the promise and challenges for translational application of novel biomarkers in the sensitive identification of drug toxicity and its mechanistic basis. Dr. Paul Watkins (HamnerUniversity of North Carolina Institute for Drug Safety Sciences) focused on insights derived from healthy volunteer studies. Some therapeutic drug regimens (e.g. acetaminophen, heparins, cholestyramine) can cause marked elevations in serum ALT but pose little risk for serious hepatotoxicity. Novel transcriptomic, metabolomic and/or proteomic biomarkers indicate that the mechanisms of hepatocyte cell death differ between these different drugs and may provide mechanistic insight into the benign and self-limited ALT abnormalities. Finally, Dr. Rob Turesky (University of Minnesota) discussed DNA and protein adducts as biomarkers of exposure to environmental and dietary toxicants. The focus was on carcinogenic heterocyclic aromatic amines formed in well-done cooked meat, such as 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP). A sensitive mass spectrometry method to biomonitor accrual of PhIP in hair was discussed, as were new approaches to biomonitor adducts formed between PhIP reactive metabolites and serum albumin as well as deoxyguanosine. Genetically Modified Animal Models for Predicting Human Drug Disposition and Response
Short Courses Metabolomic Profiling as a Tool for Identifying Novel Drug-Target Interactions
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The objectives of this short course, chaired by Dr. David Wishart (Department of Biological Sciences at the University of Alberta), were 1) to provide the latest information on novel methodologies, software and databases to perform metabolomic studies for xenobiotic metabolism and 2) to discuss and provide examples on how metabolomics can be used to better understand drug and xenobiotic metabolism. Dr. John Lindon (Department of Biological Chemistry at the Imperial College London) began with a lecture on Metabolic Phenotyping Technologies and Their Expanding Applications in Medicine. The second lecture, Stable Isotope Resolved Metabolomics in Cells, Tissue and Animal Models: A Tool for Evaluating Response to Cancer Therapeutic Agents, was then presented by Dr. Andrew Lane (The James Graham Brown Cancer Center, University of Louisville). After a brief break, Dr. Theodore Sana (Agilent Technologies, Life Sciences Group) presented on Metabolomic Profiling as a Tool for Identifying Novel Drug-Target Reactions. Dr. David Wishart closed the session with a lecture on Metabolomics and Xenobiotics.
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In his introduction, Session Chair, Dr. Xinxin Ding (Wadsworth Center, New York State Department of Health) remarked that numerous genetic mouse models are available and can be helpful for prediction of drug disposition and/or response in humans. He also stressed the need to thoroughly characterize the animal models in order to avoid misinterpretation of results. Three speakers were selected from a large number of candidates recommended by the program committee. The first speaker, Dr. Frank Gonzalez (National Cancer Institute) could not attend the meeting because of the United States government shutdown. A former associate, Dr. Xiaochao Ma (University of Pittsburgh) also a co-author of the
studies presented, delivered the lecture for Dr. Gonzalez on pregnane x receptor and peroxisome proliferatoractivated receptor a-humanized mice. Dr. Ma also incorporated new results on drug response in the PXR-humanized model from his own lab. The second speaker, Dr. Robert Tukey (University of California, San Diego) described novel mouse models with tissuespecific knockout of the Ugt1 gene and studies on the role of intestinal and hepatic glucuronidation in chemotherapy-induced toxicity by irinotecan (CPT-11). The third speaker, Dr. John Schuetz (St. Jude Children’s Research Hospital), presented studies of a murine model with absence of the porphyrin exporter, Abcg2, and findings of impaired N-MYC leukemogenesis and self-renewal of N-MYC expressing hematopoietic progenitors in the Abcg2 knockout mouse.
Model Systems and Methods for Assessing Uptake and Efflux of Small Molecules
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The objectives of this short course, chaired by Dr. Reina Bendayan (University of Toronto), were 1) to provide cutting-edge information on in vitro and in vivo methodologies as well as model systems used for the assessment of the permeability of small therapeutic molecules in key organs such as the liver, intestine, kidney, brain as well as skeletal muscle, and 2) to discuss the integration of the various experimental methods into translational Pharmacokinetic (PK) and Pharmacodynamic (PD) models. Dr Matt Soars (Bristol Myers Squibb), the first speaker of the session, addressed the use of novel in vitro tools for the study of drug transport and how the application of these tools can guide early drug discovery and development. Dr. Peter Webborn (AstraZeneca R&D) covered key pharmacokinetic concepts involved in hepatic drug disposition and the limitations of using in vitro liver cell systems to predict hepatic metabolic clearance. Dr. Rommel Tirona (London Health Sciences Center – University Hospital) discussed the use of in vitro and in vivo models for the evaluation of drug distribution and transport into the skeletal muscle and specifically addressed potential drug uptake mechanisms involved in statin-associated myopathy. Dr. Amin RostamiHodjegan (University of Manchester) summarized the integration of in vitro drug transport information into intestinal and hepatic models of drug disposition and within the physiological based pharmacokinetics (PBPK)
ISSX President Bill Smith and President-Elect/Secretary John Miners pose with the Stanley Cup at the Hockey Hall of Fame
- in vitro-in vivo extrapolation (IVIVE) framework. Finally, Dr. Bendayan ended the session with an overview and discussion of the use, advantages, and disadvantages of in vitro, in situ and in vivo models available for the study of drug transport in the brain specifically across the blood-brain barrier (brain microvessel endothelial cells) and glial cells (astrocytes and microglia). Strategies and Techniques for Predicting Human Drug Metabolism and Drug-Drug Interactions This course was developed and co-chaired by Dr. Olavi Pelkonen (University of Oulu) and by Dr. Uwe Fuhr (Uniklinik Köln). The objectives of this short course were 1) to survey current and emerging in vitro and in silico tools to assess interactions between xenobiotics and macromolecules metabolizing and transporting them, and 2) to describe modelling and simulation approaches to predict the in vivo consequences of in vitro measurable interactions, both in the context of the multiple pathways. Dr. Tommy B. Andersson (AstraZeneca) described several novel in vitro cellbased techniques used by the pharmaceutical industry, incorporating metabolic and transporting competence to predict in vivo ADME properties of new chemical entities. Dr. Frederic Bois (Université de Technologie de Compiègne) described a novel conceptual and computational approach based on physiologically based pharmacokinetic modelling coupled with a systems biology approach to estimate the interaction potential of multiple substances. Dr. Sebastian Frechen (University of Cologne) guided the attendees through the top-down modeling of the dynamic inhibition of liver and gut wall CYP3A, illustrating the vast potential of current tools integrating physiological components in classical parameter estimation. Dr. Nina Isoherranen (University of Washington) provided several examples of current literature to predict complex pharmacokinetic interactions for multiple inhibitors and inhibited pathways. The presentations demonstrated that major progress is being made, with the adoption of multiple experimental, conceptual, and computational tools, to predict quantitatively the interaction potential of a few or many drugs at a level of complexity which approaches the real life treatment of patients. Continued on next page
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Left to Right: Ann Daly, Nico Vermeulen, Rachel Tyndale, and 10th International ISSX Meeting Chair, Denis Grant.
Application of Novel Mass Spectrometric Methods to Drug Metabolism and Pharmacokinetics Studies
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The objectives of this short course were 1) to provide information about the current and novel liquid chromatography-mass spectrometry (LC-MS) based techniques available to generate drug metabolism and pharmacokinetics information as part of small molecule/peptide drug discovery and development and 2) to provide examples of applications of novel mass spectrometry techniques for quantification of drugs/ metabolites in discovery, non-regulated and regulated studies as well as methods for metabolite structural elucidation and reactive metabolite screening. Dr. Walter Korfmacher (Genzyme/Sanofi) opened the session with a lecture on Mass Spectrometry in a Drug Discovery Setting: Utility and Issues. Session Chair, Dr. Ragu Ramanathan (QPS) followed with Integrating Drug Metabolism and Pharmacokinetics Studies Using High Resolution Mass Spectrometry. Attendees learned more about Novel LC-MS Techniques for Reactive Metabolite Screening from Dr. Raju Subramanian (Amgen). Dr. Steve E. Unger (Worldwide Clinical Trials) closed the session with a presentation on LC-MS Applications in Regulated Bioanalysis.
Left to Right: ISSX President, Bill Smith with Zhuohan Hu and Yuichi Sugiyama.
received a plaque and an honorarium. The award recipients were: Pre-Doctoral Awards • First Place: Melanie Rouleau for the poster A6 entitled, “Dual role for UDP glucuronosyltransferase (UGT) 1A splice variant forms 2 (i2) in defining pharmacological response and in the oxidative stress pathway.” • Second Place: Isabelle Laverdiere for the poster A3 entitled, “The importance of 5α-reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer.” • Third Place: Mari Hashimoto for the poster A5 entitled, “Dual role for UDP glucuronosyltransferase (UGT) 1A splice variant forms 2 (i2) in defining pharmacological response and in the oxidative stress pathway.” Post-Doctoral Awards
ISSX Poster Awards
• First Place: Wendy A. Teft for the poster A10 entitled, “ABCC5 modulates systemic exposure of SN-38glucoronide in metastatic colorectal cancer patients treated with irinotecan.”
ISSX encourages high-quality research and recognizes distinguished poster presentations by young scientists in both the pre-doctoral and postdoctoral categories during the meeting.
• Second Place: Jessica K. Rieger for the poster A12 entitled, “ADME-related micrornas in human liver: association with non-genetic factors and effects on drug metabolism.”
All posters accepted as finalists in the competition were reviewed and rated by the Poster Awards Committee on the basis of Significance of Research Problem; Experimental Approach; Soundness of Conclusions; and Clarity of Presentation.
• Third Place: Soo Jin Oh for the poster A8 entitled, “Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM-IDA-EPI method.”
Meeting Chair Denis Grant announced the awards to pre-doctoral and postdoctoral finalists for best poster presentation in those categories. The winners each
Congratulations to all poster award recipients and finalists. Continued on next page
ISSX Travel Grants Travel grants were made available for student and postdocs as well as scientists from disadvantaged nations to attend the 10th International ISSX Meeting. ISSX recognizes the considerable benefit that scientists from disadvantaged nations, students, and others can gain from attending this important meeting and is proud to continue the travel grant program. The recipients of these grants provided the following summaries of their experiences at the 10th International ISSX Meeting.
Prashant Musmade It was a really great honor to be part of the 10th International ISSX meeting held on September 29th– October 3rd, 2013 in Toronto, Ontario, Canada. The researchers and experts from academia, industry and exhibitors whose expertise in the areas of drug metabolism, pharmacokinetics, and toxicity studies were assembled together. Various lectures, short courses, plenary sessions, industry-sponsored symposia were the highlights of the meeting. The poster sessions were unique and covered all the aspects of drug disposition and metabolism. Various research works presented during the poster sessions gave me an opportunity to interact with worldwide scientists. I presented a poster in the area of herbaldrug interaction entitled, “Pre-clinical evidence of life-threatening pharmacokinetic interaction between quercetin and methotrexate.” ISSX provided me the exceptional platform to interact with experts in the field of metabolism and pharmacokinetic of xenobiotics by providing the financial assistance. Experts’ opinion gained at this meeting will definitely help in my future scientific research. This conference was the best experience of my life for thinking about the research aspects in drug disposition, responses and toxicity aspects. In addition, the visit to Toronto, Canada was certainly a rewarding experience for me.
Raúl Alejandro Salazar González
Cuiping Yang
ISSX Travel Grant recipient, Cuiping Yang, stands with her poster during a poster presentation session.
This report sponsored by a grant from Eli Lilly & Company.
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Thanks to the Committee of the 10th International ISSX meeting to award me a generous travel grant plus a free meeting registration, which makes it possible for me to attend such an important meeting in my research field. It is also my first time to attend an international meeting abroad and present my work as a poster. It is great to meet so many experts during this meeting and to witness excellent speeches conveying the most intelligent ideas and the latest progress. The Student and New Investigator Reception was also a valuable activity for us to share ideas. Luckily, I met several attendees in the same research field as me and we exchanged personal information for further contact. Participation in such a great meeting broadens my mind and activates certain ideas for my own future research work. When back in China, I shared my experiences and gains with my colleagues and friends. Besides, Toronto is such a fabulous city. I was impressed with the friendly and passionate people, boundless Ontario Lake, impressive city sightseeing, and majestic Niagara Falls.
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The 10th International ISSX meeting held in Toronto, Canada turned out to be a great experience. The scientific program was very well structured, with very interesting sessions covering all the fields on this specific area of knowledge; the speakers presented really interesting talks and showed their vast expertise in their respective fields. All the organization from the abstract submission through the end of the meeting was superb. The sponsor symposia and the exhibit booths were an interesting part of the meeting; it is helpful to know all the possibilities we have in terms of new products and technologies that the companies have to offer. The poster sessions showed very interesting works in many different areas and a wide diversity of universities and institutions which helped me to catch up with the latest advances in the field. Attending this meeting helped me to personally
present our results and explore new areas and topics in order to increase collaborations and get involved in new and different projects in relation to the latest developments in the field.
Submit an Abstract for the 19th North American ISSX / 29th JSSX Meeting The meeting offers multiple options for attendee involvement and peer recognition: 1. Present your work in one of three abstract poster sessions. General abstract sessions for poster presentations will be held Monday, October 20 - Wednesday, October 22.
2. Present your work as a lecture for other attendees in a parallel symposium at the meeting. This meeting features the opportunity for several fifteenminute lectures during the meeting. To be considered, select the option for Oral Presentation when submitting your abstract.
3. Compete in the Student Poster Awards Competition. This competition is open to the categories of Predoctoral and Postdoctoral students. Six finalists from each category will be chosen to present posters throughout the meeting.
All accepted abstracts will be included in a supplemental issue of Drug Metabolism Reviews and the ISSX Online Abstracts Database.
www.issx.org/jssx-issx/abstracts
President’s Message Continued from page 1
may recall the highly successful joint ISSX-JSSX meeting in Maui in 2005. I urge ISSX members to support these meetings. Remember, ISSX members receive substantial discounts on meeting registration fees. If you have not yet renewed your membership for 2014, I encourage you to do so. I look forward to seeing you in San Francisco. John O. Miners President International Society for the Study of Xenobiotics
ISSX Career Center Searching for experts in the field of drug metabolism, pharmacokinetics, pharmacodynamics, and other related areas? The ISSX Career Center job board is your premier resource to find skilled applicants. •C reate Your Company Profile free of charge and explain the organization and work environment in detail. •W hen your positions are advertised on the ISSX Career Center, an e-mail advertising the position is sent automatically to job seekers who have requested notifications about opportunities matching their search criteria. •B rowse résumés for free and pay only for the résumés that you select. Post your jobs online today! When you use the ISSX Career Center, you ensure that your open positions are advertised in the right place. Visit www.issx.org/careercenter.
Nominate a colleague for the 19th North American ISSX Meeting Awards.
Visit www.issx.org/awards/nominations to learn more and submit a nomination.
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North American Scientific Achievement Award Presented to an ISSX member who has made major scientific contributions to the field within the North American region. The purpose of this award is to recognize meritorious contributions by senior or midcareer scientists that have had a major impact on research in the field. The North American Scientific Achievement Award is named in Honor of Ronald W. Estabrook and is sponsored by XenoTech.
North American New Investigator Award—Presented to an ISSX member who has made significant contributions to the field during their early career years (normally within 5–10 years from the time of receiving his/ her highest earned degree). The purpose of these awards is to encourage and recognize developing scientists who are active in the field within the North American region. The North American New Investigator Award is named in honor of James R. Gillette.
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Nominations are now being accepted for the following awards to be presented at the 19th North American ISSX / 29th JSSX Meeting in October, 2014. The two awards to be presented at this meeting are:
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Advertise with ISSX The quarterly ISSX Newsletter is an online publication featuring Society updates, scientific articles of interest, book reviews, summaries of ISSX meeting proceedings, and more. This publication is designed to update the ISSX membership on the activities and events of the organization and to provide an information forum. Not only is the ISSX Newsletter promoted directly to all ISSX Members, but, as of 2012, it is also available to anyone who visits the ISSX Web site.
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