Updated on 2022/06/17

写真a

 
NAKAI Yasuhiro
 
Organization
Nagoya University Hospital Designated professor
Title
Designated professor

Degree 1

  1. 博士(薬学) ( 2008.3   名古屋市立大学 ) 

Research Areas 1

  1. Life Science / Medical technology assessment

Research History 2

  1. Nagoya University   Hospital, Exploratory Oncology Research & Clinical Trial   Designated professor

    2019

  2. Taisho Pharmaceutical co.ltd.   Development headquarter   Deputy head

    2007 - 2018

 

Papers 9

  1. Protocol for a Phase 1, Open-Label, Multiple-Center, Dose-Escalation Study to Evaluate the Safety and Tolerability of ADR-001 in the Treatment of Immunoglobulin A Nephropathy.

    Tanaka A, Furuhashi K, Fujieda K, Maeda K, Saito S, Mimura T, Saka Y, Naruse T, Ishimoto T, Kosugi T, Kinoshita F, Kuwatsuka Y, Shimizu S, Nakai Y, Maruyama S

    Frontiers in medicine   Vol. 9   page: 883168   2022

     More details

    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.3389/fmed.2022.883168

    PubMed

  2. Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia.

    Kitoh H, Matsushita M, Mishima K, Nagata T, Kamiya Y, Ueda K, Kuwatsuka Y, Morikawa H, Nakai Y, Ishiguro N

    PloS one   Vol. 15 ( 4 ) page: e0229639   2020

     More details

    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1371/journal.pone.0229639

    PubMed

  3. In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor International journal

    Yukihiro Chino, Masatoshi Hasegawa, Yoshiki Fukasawa, Yoko Mano, Kagumi Bando, Atsunori Miyata, Yasuhiro Nakai, Hiromi Endo, Jun-ichi Yamaguchi

    XENOBIOTICA   Vol. 47 ( 4 ) page: 314 - 323   2017.4

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:TAYLOR & FRANCIS LTD  

    1. We evaluated potential in vitro drug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively.
    2. Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC50 value of 58.3 mu M, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72hrs weakly induced CYP3A4 at a concentration of 10 mu M, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1-10 mu M.
    3. An in vitro transport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC50 value of 93.1 mu M, but those for other transporters are greater than 100 mu M.
    4. Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters.

    DOI: 10.1080/00498254.2016.1193913

    Web of Science

    PubMed

  4. Metabolite profiling and enzyme reaction phenotyping of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in humans International journal

    Atsunori Miyata, Masatoshi Hasegawa, Kenji Hachiuma, Haruyuki Mori, Nobuko Horiuchi, Akiko Mizuno-Yasuhira, Yukihiro Chino, Shigeji Jingu, Soichi Sakai, Yoshishige Samukawa, Yasuhiro Nakai, Jun-ichi Yamaguchi

    XENOBIOTICA   Vol. 47 ( 4 ) page: 332 - 345   2017.4

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:TAYLOR & FRANCIS LTD  

    1. To understand the clearance mechanism of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, we investigated its human metabolite profile and metabolic enzymes responsible for the primary metabolic pathways in human using reaction phenotyping.
    2. Sixteen metabolites of luseogliflozin were found in human plasma and/or urine and their structural information indicated that the drug was metabolized via multiple metabolic pathways. The primary metabolic pathways involve (1) O-deethylation to form M2 and subsequent glucuronidation to form M12, (2) omega-hydroxylation at ethoxy group to form M3 followed by oxidation to form the corresponding carboxylic acid metabolite (M17) and (3) direct glucuronidation to form M8.
    3. The reaction phenotyping studies indicated that the formation of M2 was mainly mediated by cytochrome P450 (CYP) 3A4/5, and subsequently M12 formation was catalyzed by UGT1A1, UGT1A8 and UGT1A9. The formation of M3 was mediated by CYP4A11, CYP4F2 and CYP4F3B, and the further oxidation of M3 to M17 was mediated by alcohol dehydrogenase and aldehyde dehydrogenase. The formation of M8 was catalyzed by UGT1A1.
    4. These results demonstrate that luseogliflozin is metabolized through multiple pathways, including CYP-mediated oxidation and glucuronidation, in human.

    DOI: 10.1080/00498254.2016.1193263

    Web of Science

    PubMed

  5. Preclinical metabolism and disposition of luseogliflozin, a novel antihyperglycemic agent International journal

    Masatoshi Hasegawa, Yukihiro Chino, Nobuko Horiuchi, Kenji Hachiuma, Masahiro Ishida, Yoshiki Fukasawa, Yasuhiro Nakai, Jun-ichi Yamaguchi

    XENOBIOTICA   Vol. 45 ( 12 ) page: 1105 - 15   2015

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:TAYLOR & FRANCIS LTD  

    1. We investigated the metabolism and disposition of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in rats and dogs, as well as in vitro metabolism in rats, dogs and humans. In addition, we studied its localization in the rat kidney.
    2. [C-14] Luseogliflozin was rapidly and well absorbed (>86% of the dose) after oral administration to rats and dogs. The drug-derived radioactivity was mainly excreted via the feces in both species.
    3. The predominant radioactivity component in the excreta was associated with the metabolites, with only a minor fraction of unchanged luseogliflozin. The major metabolites were two glucuronides (M8 and M16) in the rats, and the O-deethylated form (M2) and other oxidative metabolites (M3 and M17) in the dogs.
    4. The in vitro metabolism in dog and human hepatocytes was significantly slower than that in the rat hepatocytes. The biotransformation in animal hepatocytes was similar to that observed in vivo. Incubation with human hepatocytes resulted in the formation of metabolites, including M2, M3, M8 and M17, via multiple metabolic pathways.
    5. [C-14] Luseogliflozin was well-distributed to its target organ, the kidney, and was found to be localized in the renal cortex, which shows SGLT2 expression. This characteristic distribution was inhibited by preinjection of phlorizin, an SGLT inhibitor, suggesting that the renal radioactivity was associated with SGLT2.

    DOI: 10.3109/00498254.2015.1042947

    Web of Science

    PubMed

  6. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria International journal

    Yukihiro Chino, Yoshishige Samukawa, Soichi Sakai, Yasuhiro Nakai, Jun-ichi Yamaguchi, Takeo Nakanishi, Ikumi Tamai

    BIOPHARMACEUTICS & DRUG DISPOSITION   Vol. 35 ( 7 ) page: 391 - 404   2014.10

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UEUA) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UEUA, suggesting that SUA decreased as a result of the increase in the UEUA. The increase in UEUA was correlated with an increase in urinary d-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UEUA is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9N, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and d-glucose. It was observed that the efflux of [C-14]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm d-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [C-14]UA by oocytes was cis-inhibited by 100 mm d-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UEUA could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. (c) 2014 The Authors. Biopharmaceutics & Drug Disposition. Published by John Wiley & Sons Ltd.

    DOI: 10.1002/bdd.1909

    Web of Science

    PubMed

  7. A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans International journal

    Akiko Mizuno-Yasuhira, Yasuhiro Nakai, Emi Gunji, Saeko Uchida, Teisuke Takahashi, Kohnosuke Kinoshita, Shigeji Jingu, Soichi Sakai, Yoshishige Samukawa, Jun-ichi Yamaguchi

    DRUG METABOLISM AND DISPOSITION   Vol. 42 ( 9 ) page: 1456 - 65   2014.9

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol T-max (time for C-max) value (TAIC/T-max). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/T-max in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/T-max in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter.

    DOI: 10.1124/dmd.114.058305

    Web of Science

    PubMed

  8. Luseogliflozin (TS-071) a Novel, Potent and Selective SGLT2 Inhibitor, Did not Affect the PK of Several Oral Diabetic Agents in Clinical Reviewed International journal

    Yasuhiro Nakai, Masaru Mutoh

    DIABETES   Vol. 61   page: A607 - A607   2012.6

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER DIABETES ASSOC  

    Web of Science

  9. 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 International journal

    Koji Kato, Hiroyuki Kusuhara, Yuji Kumagai, Ichiro Ieiri, Haruyuki Mori, Sumito Ito, Yasuhiro Nakai, Kazuya Maeda, Yuichi Sugiyama

    PHARMACOGENETICS AND GENOMICS   Vol. 22 ( 5 ) page: 344 - 54   2012.5

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives Multidrug resistance-associated protein 2 (MRP2; ABCC2) is an ATP-binding cassette transporter that mediates the efflux of anionic drugs and phase II metabolites. Our aim was to elucidate the impact of a single nucleotide polymorphism, rs12762549 (G > C), on the in-vivo activity of MRP2.
    Methods Plasma specimens collected from 18 healthy volunteers were subjected to an untargeted metabolomic analysis using liquid chromatography-mass spectrometry. The role of MRP2 in the disposition of substances of interest was then examined in vivo in Mrp2-deficient mutant rats (Eisai hyperbilirubinemic rats; EHBRs) and in vitro in human MRP2-expressing membrane vesicles.
    Results A multivariate analysis model using liquid chromatography-mass spectrometry data sets successfully differentiated the GG and the CC genotypes of rs12762549. The C allele is associated with the basal plasma levels of the five phase II metabolites of genistein and dihydrogenistein. Such phase II metabolites were also accumulated in EHBR, compared with normal rats, partly because of the reduced biliary excretion. Following oral administration of genistein and daidzein, the plasma concentrations of total genistein and total daidzein, which were mainly accounted for by sulfoglucuronide conjugates, were markedly higher in EHBR than in normal rats. ATP-dependent uptake of sulfoglucuronides and glucuronides of the isoflavonoids was observed only in MRP2-expressing membrane vesicles.
    Conclusion MRP2 plays a significant role in preventing the accumulation of phase II metabolites of isoflavonoids. The rs12762549 is associated with an interindividual difference in the plasma levels of MRP2 substrates, phase II metabolites of isoflavonoids, suggesting that this single nucleotide polymorphism is associated with variations in in-vivo MRP2 activity. Pharmacogenetics and Genomics 22:344-354 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

    DOI: 10.1097/FPC.0b013e3283517012

    Web of Science

    PubMed

▼display all

MISC 8

  1. SGLT2阻害剤ルセオグリフロジンの代謝経路及び代謝酵素 International journal

    地野之浩, 宮田敦徳, 長谷川雅俊, 八馬賢次, 森治之, 堀内伸子, 安平明公, 神宮茂司, 坂井壮一, 寒川能成, 中井康博, 山口順一, 佐々木敬, 清野裕

    糖尿病   Vol. 58 ( Suppl.1 ) page: S - 174   2015.4

     More details

    Language:Japanese  

    J-GLOBAL

  2. 選択的SGLT2阻害剤ルセオグリフロジンのヒト薬物トランスポーターを介した薬物間相互作用の評価 International journal

    深沢芳樹, 長谷川雅俊, 間野陽子, 地野之浩, 坂東香久美, 宮田敦徳, 中井康博, 山口順一

    日本薬学会年会要旨集(CD-ROM)   Vol. 134年会 ( 4 ) page: 128 - 128   2014.3

     More details

    Language:Japanese  

    J-GLOBAL

  3. 早期探索臨床試験への企業からの期待 International journal

    中井康博

    HAB研究機構学術年会プログラム・要旨集   Vol. 19th   page: 72 - 74   2012.5

     More details

    Language:Japanese  

    J-GLOBAL

  4. 新規選択的SGLT2阻害剤TS‐071薬物相互作用の検討 International journal

    武藤賢, 水井信夫, 中井康博, 寒川能成, 坂井荘一, 渡辺隆

    臨床薬理   Vol. 42 ( Suppl. ) page: S345 - S345   2011.10

     More details

    Language:Japanese  

    J-GLOBAL

  5. Characterization of novel non-selective P450 inhibitor MDPP International journal

    Iida Izumi, Inatani Shouko, Miyata Atsunori, Kanamaru Akiko, Toki Hidetoh, Kamigaso Shunsuke, Nakai Yasuhiro

    Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics   Vol. 25 ( 0 ) page: 297 - 297   2010

     More details

    Language:Japanese   Publisher:The Japanese Society for the Study of Xenobiotics  

  6. COMPARISON BETWEEN IN VITRO BIDIRECTIONAL PERMEABILITY STUDY FOR HUMAN MDR1 AND IN VIVO RAT CENTRAL NERVOUS SYSTEM PENETRATION TO INVESTIGATE SPECIES DIFFERENCE International journal

    Otake Katsumasa, Iida Izumi, Toki Hidetou, Sasaki Hana, Kawakita Yasunori, Ohmichi Mari, Nakai Yasuhiro, Urano Hidetoshi

    Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics   Vol. 25 ( 0 ) page: 161 - 161   2010

     More details

    Language:Japanese   Publisher:The Japanese Society for the Study of Xenobiotics  

  7. METABONOMIC APPROACH FOR IDENTIFYING ENDOGENOUS AND FOOD-DERIVED SUBSTRATES OF MRP2 IN RATS International journal

    Kato Koji, Kusuhara Hiroyuki, Mori Haruyuki, Nakai Yasuhiro, Sugiyama Yuichi

    Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics   Vol. 25 ( 0 ) page: 147 - 147   2010

     More details

    Language:Japanese   Publisher:The Japanese Society for the Study of Xenobiotics  

  8. CROSSTALK OF MAIN CYTOCHROME P450 ISOZYME FOR METABOLISM-DEPENDENT INHIBITION International journal

    Inatani Syoko, Okumura Hirotoshi, Nakai Yasuhiro, Urano Hidetoshi

    Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics   Vol. 25 ( 0 ) page: 211 - 211   2010

     More details

    Language:Japanese   Publisher:The Japanese Society for the Study of Xenobiotics  

▼display all