Sugiyama Laboratory

Many drug candidate compounds are synthesized in the early stage of a drug discovery. For these drug candidates, binding affinities to the target molecule (related to pharmacodynamics), rates of metabolism and membrane permeabilities (related to pharmacokinetics) will be studied by in vitro experiments. By comparing the various parameters obtained in these experiments, drug candidates will be selected and introduced into clinical trials. However, efficacies expected from animal experiments and in vitro experiments are not always reproducible in clinical trials, and it is also true that most of drug candidates drop out before the market. Since clinical trials require a lot of money, it is very important to select good drug candidates before going to the stage of clinical trials. RIKEN established Sugiyama Laboratory to promote the construction of an integrated support system for efflcient drug discovery. In Sugiyama Laboratory, we will establish a new methodology to select a reasonable drug candidates in the early stages of drug discovery. In particular, mathematical models that incorporate parameters obtained from a variety of in vitro screening will be constructed, which can be used for the quantitative simulation of pharmacokinetics and pharmacodynamics. Thus, before entering the clinical trials, we will accurately predict the efficacy of each drug candidate in human. In addition, PET molecular imaging which enables the real-time and non-invasive quantification of PET-probed drugs and drug candidates in organs should be useful for the optimization of our mathematical models. In the future, our research will lead to the development of drugs that have wide therapeutic ranges or that can be less affected by drug-drug interactions, inter-individual variation and disease states.

Research Subjects

• In vitro - in vivo extrapolation (IVIVE) of pharmacokinetic parameters
• Prediction of drug-drug interaction (DDI)
• Evaluation of interindividual variability in pharmacokinetics and pharmacodynamics
• Establishment of guidelines for exploratory new drug studies (eIND), microdose (MD) clinical studies and molecular imaging clinical studies

Publications

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 the hepatic clearance and intestinal absorption."
   Biopharm Drug Dispos. 2012 Oct 31. doi: 10.1002/bdd.1823. [Epub ahead of print] PMID: 23115084
2. Yoshida K, Maeda K, Sugiyama Y.:
   "Hepatic and Intestinal Drug Transporters: Prediction of Pharmacokinetic Effects Caused by Drug-Drug Interactions and Genetic Polymorphisms."
   Annu Rev Pharmacol Toxicol. 2012 Nov 8. [Epub ahead of print] PMID: 23140240
3. Ieiri I, Doi Y, Maeda K, Sasaki T, Kimura M, Hirota T, Chiyoda T, Miyagawa M, Irie S, Iwasaki K, Sugiyama Y.:
   "Microdosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1), and Interaction (Grapefruit Juice) Profiles of Celiprolol Following the Oral Microdose and Therapeutic Dose."
   J Clin Pharmacol, 52: 1078-89 (2012)
4. Tachibana T, Kato M, Sugiyama Y.:
   "Prediction of nonlinear intestinal absorption of CYP3A4 and P-glycoprotein substrates from their in vitro Km values."
   Pharm Res, 29: 651-68 (2012)
5. Shimizu K, Takashima T, Yamane T, Sasaki M, Kageyama H, Hashizume Y, Maeda K, Sugiyama Y, Watanabe Y, Senda M
   "Whole-body distribution and radiation dosimetry of [11C]telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3."
   Nucl Med Biol, 39(6): 847-53 (2012)
6. Ijuin R, Takashima T, Watanabe Y, Sugiyama Y, Suzuki M.:
   "Synthesis of [(11)C]dehydropravastatin, a PET probe potentially useful for studying OATP1B1 and MRP2 transporters in the liver."
   Bioorg Med Chem, 15; 20(12): 3703-9 (2012)
7. Ieiri I, Fukae M, Maeda K, Ando Y, Kimura M, Hirota T, Nakamura T, Iwasaki K, Matsuki S, Matsuguma K, Kanda E, Deguchi M, Irie S, Sugiyama Y.:
   "Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing."
   Int J Clin Pharmacol Ther, 50(10): 689-700 (2012)
8. Kusuhara H, Miura M, Yasui-Furukori N, Yoshida K, Akamine Y, Yokochi M, Fukizawa S, Ikejiri K, Kanamitsu K, Uno T, Sugiyama Y.:
   "Effect of Coadministration of Single and Multiple Doses of Rifampicin on the Pharmacokinetics of Fexofenadine Enantiomers in Healthy Subjects."
   Drug Metab Dispos, 41(1): 206-13 (2013)
9. Kudo T, Hisaka A, Sugiyama Y, Ito K.:
   "Analysis of the Repaglinide Concentration Increase Produced by Gemfibrozil and Itraconazole Based on the Inhibition of the Hepatic Uptake Transporter and Metabolic Enzymes."
   Drug Metab Dispos, 41(2): 362-71 (2013)
10. Kato K, Kusuhara H, Kumagai Y, Ieiri I, Mori H, Ito S, Nakai Y, Maeda K, Sugiyama Y.:
    "Association of multidrug resistance-associated protein 2 single nucleotide polymorphism rs12762549 with the basal plasma levels of phase II metabolites of isoflavonoids in healthy Japanese individuals."
    Pharmacogenet Genomics, 22(5): 344-54 (2012)