Prof. Yuichi Sugiyama – Extended Clearance Concept and PBPK Modeling for Predicting Transporter/Enzyme-Mediated Complex Drug-Drug Interactions

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  •  Organizer: Optivia Biotechnology Inc.

    Time: Wed, Mar 22, 2017 1:00 PM - 2:30 PM PDT

    Cost: Free

  • Even when drugs ultimately undergo metabolism and/or biliary excretion in the liver, their elimination rate is sometimes determined by the hepatic uptake rate mediated by uptake transporters. Elucidation of the rate-determining process in the overall hepatic elimination of drugs is therefore critical for predicting their hepatic clearance, and their systemic and regional exposures. I will show with you how to understand the so-called “Extended clearance concept (ECC)”(1) and to establish a physiologically based pharmacokinetic (PBPK) model(2) that includes that the passive transport and transporter-mediated membrane transport and enzyme-mediated metabolism processes.  I will also share with you how to investigate the effect of changes in transporter (influx, efflux) function and metabolizing enzyme function on the pharmacokinetics of drugs in the blood and the liver and, ultimately, the pharmacological and/or toxicological effects (1-4).  Most recently, ECC has been used by a few pharmaceutical industries to predict the predominant clearance mechanism based on physiocochemical properties and passive membrane permeability and this may aid in selecting the appropriate preclinical studies for optimizing the drug exposure (5,6).

    For drugs, the target molecule of which is inside the cells, the efflux transporter is the determinant for their pharmacological effect or adverse reactions even though it had negligible impact in the plasma concentrations.  Because of difficulty in quantitative evaluation of the subsequent efflux process, the transporters playing key roles in the efflux process remains unclear in humans.  Development of probe substrates applicable to the PET imaging will elucidate the quantitative relationship between the transport activities and drug response (7). 

    This study proposed a method to optimize in vivo PBPK parameters in hepatic uptake/efflux/enzyme transporter-mediated DDIs based on several important drug dependent in vitro parameters on transport, metabolism and inhibition(2).



    1. Shitara Y, Maeda K, Ikejiri K, Yoshida K, Horie T, Sugiyama Y. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption. Biopharm Drug Dispos, 34: 45-78 (2013)
    2. Yoshikado T, Yoshida K, Kotani N, Nakada T, Asaumi R, Toshimoto K, Maeda K, Kusuhara H, Sugiyama Y. Quantitative analyses of hepatic OATP-mediated interactions between statins and inhibitors using PBPK modeling with a parameter-optimization method. Clin Pharmacol Ther.100:513-523(2016)
    3. Watanabe T, Kusuhara H, Sugiyama Y. Application of physiologically based pharmacokinetic modeling and clearance concept to drugs showing transporter-mediated distribution and clearance in humans. J Pharmacokinet Pharmacodyn.37(6):575-90 (2010).
    4. Yoshida K, Maeda K, Sugiyama Y. Hepatic and intestinal drug transporters: prediction of pharmacokinetic effects caused by drug-drug interactions and genetic polymorphisms. Annual review of pharmacology and toxicology. 53:581-612 (2013).
    5. Varma MV,Steyn SJAllerton CEl-Kattan AF. Predicting clearance mechanism in drug discovery: Extended clearance classification system (ECCS). Pharm Res. 32:3785-802 (2015) .
    6. Camenisch GP. Drug disposition classification systems in discovery and development: A comparative review of the BDDCS, ECCS and ECCCS Concepts.Pharm Res.33:2583-93 (2016)
    7. Takashima T, Kitamura S, Wada Y, Tanaka M, Shigihara Y, Ishii H, Ijuin R, Shiomi S, Nakae T, Watanabe Y, Cui Y, Doi H, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y and Watanabe Y. PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me. J Nucl Med 53:741-748 (2012).
  • Prof. Yuichi Sugiyama

    Dr. Sugiyama received a Ph.D. from University of Tokyo, School of Pharmacy in 1978. He started his academic career in 1974 as a Research Associate of the University of Tokyo. He was promoted to the rank of Associate Professor in 1989 and of Professor in 1991. He retired from the University of Tokyo in 2012 and has continued his studies as head of the Sugiyama Laboratory at the RIKEN Innovation Center.

    Dr. Sugiyama is acknowledged as a world-leader in the fields of physiologically based pharmacokinetics and membrane transporters. His work on physiologically based pharmacokinetics has been pivotal for quantitative in vitro – in vivo extrapolation, especially the development of models for the prediction of drug clearance and the magnitude of inhibitory drug-drug interactions in humans. Further, his studies on membrane transporters, which encompass functional and kinetic characterization, and the impact of genetic variation, have been fundamental to our understanding of the role of transporters in drug disposition.

    Dr. Sugiyama has thus produced a remarkable body of scientific work. He is the author of 665 original articles, 65 review articles, and 29 book chapters. Dr. Sugiyama has been the recipient of many prestigious awards, including the AAPS Award in 2003, PSWC Research Achievement Award in 2007, ISSX Asia Pacific Scientific Achievement Award in 2008, FIP Host-Madsen Gold Medal in 2009, Medal with Purple Ribbon given by Government of Japan in 2010, BB Brodie Award from ASPET in 2012, Rawls-Palmer Progress in Medicine Award from ASCPT in 2014, and the RT Williams Distinguished Scientific Achievement Award from ISSX in 2013. In addition to his scientific work, Dr Sugiyama has held leadership positions in several scientific organizations. In particular, he has served as the chairman of board of Pharmaceutical Sciences (BPS) of FIP and Presidents of ISSX and JSSX and strongly promoted worldwide drug metabolism, disposition, transport research.