In vivo analysis of intestinal drug absorption using adaptor/efflux transporter gene deficient mice

• Project/Area Number: 22790152
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: Kanazawa University
• Principal Investigator: SUGIURA Tomoko 金沢大学, 薬学系, 助教 (70542190)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: トランスポーター / アダプター / 消化管吸収 / タンパク質間相互作用 / PDZK1 / BCRP / OATP1A2 / 薬物動態学 / アダプタータンパク質 / 薬物生態学

Research Abstract

Transporter adaptor protein PDZK1regulates several influx transporters(PEPT1and OCTN2) in small intestine, and their expression on the apical membrane is diminished in pdzk1gene knockout mice(pdzk1^<-/->). In addition, we have identified that PDZK1regulates the expression of organic anion transporting polypeptide OATP1A and intestinal absorption of its substrate, estrone-3-sulfate. In the present study, we attempted to use pdzk1^<-/-> mice to functionally identify influx transporters responsible for intestinal absorption of cimetidine. Contrary to our expectation, the expression level of intestinal efflux transporter for cimetidine, BCRP, was significantly decreased in pdzk1^<-/-> mice, and plasma concentration of cimetidine after oral administration to pdzk1^<-/-> mice was higher than that in wild-type mice. Taken together, these findings demonstrate that PDZK1plays a pivotal role in the apical localization of both influx transporters and efflux transporter in small intestine.

Research Products

• [Journal Article] Muscle contraction increases carnitine uptake via translocation of OCTN2 (2012)
  • Author(s): Furuichi Y.
  • Journal Title: Biochem Biophys Res Commun Volume: Vol.418 Issue: 4 Pages: 774-779
  • DOI: 10.1016/j.bbrc.2012.01.101
  • Peer Reviewed
• [Journal Article] DZK1 regulates breast cancer resistance protein in small intestine (2011)
  • Author(s): Shimizu, T., Sugiura, T., Wakayama, T.,Kijima, A., Nakamichi, N., Iseki, S.,Silver, D.L., Kato, Y
  • Journal Title: Drug Metab. Dispos Volume: 39 Issue: 11 Pages: 2148-2154
  • DOI: 10.1124/dmd.111.040295
  • Peer Reviewed
• [Journal Article] PDZ adaptors : their regulation of epithelial transporters and involvement in human disease (2011)
  • Author(s): Sugiura T, Shimizu T, Kijima A, Minakata S, Kato Y
  • Journal Title: J Pharm Sci Volume: 100(9) Issue: 9 Pages: 3620-3635
  • DOI: 10.1002/jps.22575
  • NAID: 120003308592
  • Peer Reviewed
• [Journal Article] Pharmacokinetics and hepatic uptake of eltrombopag, a novel platelet-increasing agent (2011)
  • Author(s): Takeuchi, K., Sugiura, T., Umeda, S.,Matsubara, K., Horikawa, M., Nakamichi, N., Silver, D.L., Ishiwata, N., Kato, Y
  • Journal Title: Drug Metab. Dispos Volume: 39 Issue: 6 Pages: 1088-1096
  • DOI: 10.1124/dmd.110.037960
  • Peer Reviewed
• [Journal Article] Pharmacokinetics and hepatic uptake of eltrombopag, a novel platelet-increasing agent. (2011)
  • Author(s): Kazuya Takeuchi, et al.
  • Journal Title: Drug Metab Dispos Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] PDZ adaptors : Their regulation of epithelial transporters and involvement in human diseases. (2011)
  • Author(s): Tomoko Sugiura, et al.
  • Journal Title: J Pharm Sci Volume: (印刷中)
  • NAID: 120003308592
  • Peer Reviewed
• [Journal Article] PDZK1 Regulates Organic Anion Transporting Polypeptide Oatp1a in Mouse Small Intestine (2010)
  • Author(s): Sugiura T, Otake T, Shimizu T, Wakayama T, Silver DL, Utsumi R, Nishimura T, Iseki S, Nakamichi N, Kubo Y, Tsuji A, Kato Y
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 25 Issue: 6 Pages: 588-598
  • DOI: 10.2133/dmpk.DMPK-10-RG-074
  • NAID: 10027743926
  • ISSN: 1347-4367, 1880-0920
  • URL: https://localhost/en/publications/82b70f67-bc79-40fb-bfb9-b02455e63ce5
  • Peer Reviewed
• [Journal Article] Functional expression of carnitine/organic cation transporter OCTN1/SLC22A4 in mouse small intestine and liver (2010)
  • Author(s): Sugiura, T., Kato, S., Shimizu, T.,Wakayama, T., Nakamichi, N., Kubo, Y.,Iwata, D., Suzuki, K., Soga, T., Asano, M., Iseki, S., Tamai, I., Tsuji, A., Kato, Y.
  • Journal Title: Drug Metab. Dispos Volume: 38 Issue: 10 Pages: 1665
  • DOI: 10.1124/dmd.110.032763
  • URL: https://pure.teikyo.jp/en/publications/bb9fb9c4-e10f-43cb-8f96-ff99ebd5fa95
  • Peer Reviewed
• [Journal Article] Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1 (2010)
  • Author(s): Kato Y, Kubo Y, Iwata D, Kato S, Sudo T, Sugiura T, Kagaya T, Wakayama T, Hirayama A, Sugimoto M, Sugihara K, Kaneko S, Soga T, Asano M, Tomita M, Matsui T, Wada M, Tsuji A
  • Journal Title: Pharm Res Volume: 27(5) Issue: 5 Pages: 832-840
  • DOI: 10.1007/s11095-010-0076-z
  • NAID: 120002224385
  • Peer Reviewed
• [Journal Article] OCTN2 is associated with carnitine transport capacity of rat skeletal muscles (2010)
  • Author(s): Furuichi Y, Sugiura T, Kato Y, Shimada Y, Masuda K
  • Journal Title: Acta Physiol Volume: 200(1) Issue: 1 Pages: 57-64
  • DOI: 10.1111/j.1748-1716.2010.02101.x
  • Peer Reviewed
• [Journal Article] PDZK1 regulates organic anion transporting polypeptide Oatpla in mouse small intestine. (2010)
  • Author(s): Tomoko Sugiura, et al.
  • Journal Title: Drug Metab Pharmacokinet Volume: 25 Pages: 588-598
  • NAID: 10027743926
  • Peer Reviewed
• [Journal Article] Functional Expression of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in mouse small intestine and liver. (2010)
  • Author(s): Tomoko Sugiura, et al.
  • Journal Title: Drug Metab Dispos Volume: 38 Pages: 1665-1672
  • Peer Reviewed
• [Presentation] Potential protective role of OCTN1/SLC22A4 in progression of dimethylnitrosamine(DMN)-induced liver fibrosis (2012)
  • Author(s): Sugiura T, Harada R, Sakai Y, Wakayama T, Kawabata S, Nakamichi N, Iseki S, Kaneko S, Kato Y
  • Place of Presentation: Hitotsubashi Hall(Tokyo, Japan)
• [Presentation] Potential protective role of OCTN1/SLC22A4 in progression of dimethilnitrosamine (DMN)-induced liver fibrosis (2012)
  • Author(s): Tomoko Sugiura, et al
  • Organizer: Past, Present and Future of Moleculr Pharmacokinetics
  • Place of Presentation: Hitotsubashi Hall (Tokyo)
• [Presentation] PDZK1による消化管排泄トランスポーターBCRPの制御と薬物動態への影響 (2011)
  • Author(s): 杉浦智子、清水卓也、若山友彦、木嶋愛、中道範隆、井関尚一、加藤将夫
  • Organizer: 第6回トランスポーター研究会年会
  • Place of Presentation: 東北大学片平さくらホール(宮城)
• [Presentation] トランスポーターoctn1遺伝子欠損マウスを用いたDMN誘発性肝線維化の解析 (2011)
  • Author(s): 杉浦智子、原田龍一、酒井佳夫、若山友彦、中道範隆、井関尚一、金子周一、加藤将夫
  • Organizer: 日本薬剤学会第26年会
  • Place of Presentation: タワーホール船堀(東京)
• [Presentation] PDZK1による消化管排出トランスポーターBCRPの制御と薬物動態への影響 (2011)
  • Author(s): 杉浦智子, 他
  • Organizer: 第6回トランスポーター研究会年会
  • Place of Presentation: 東北大学片平さくらホール(宮城)
• [Presentation] Adaptor protein PDZK1 affects drug absorption by regulating multiple small intestinal transporters (2010)
  • Author(s): Sugiura T, Kijima A, Shimizu T, Nakamichi N, Tsuji A, Kato Y
  • Organizer: 2010FIP PSWC/AAPS Annual Meeting and Exposition
  • Place of Presentation: New Orleans Ernest N. Morial Convention Center(USA)
• [Presentation] アダプターによる消化管トランスポーターの機能・発現制御と薬物動態への影響 (2010)
  • Author(s): 杉浦智子、中道範隆、加藤将夫
  • Organizer: 第5回トランスポーター研究会
  • Place of Presentation: 東京医科大学病院臨床講堂(東京)
• [Presentation] 血小板増多剤eltrombopagの肝取り込み機構 (2010)
  • Author(s): 杉浦智子、竹内和也、松原和貴、梅田沙希、中道範隆、加藤将夫
  • Place of Presentation: あわぎんホール徳島県郷土文化会館(徳島)
• [Presentation] 新規血小板増多剤eltrombopagの肝取り込み機構 (2010)
  • Author(s): 杉浦智子, 他
  • Organizer: 日本薬剤学会第25年会
  • Place of Presentation: あわぎんホール徳島県郷土文化会館(徳島県)
• [Presentation] アダプタータンパク質による消化管トランスポーターの機能・発現制御と薬物動態への影響 (2010)
  • Author(s): 杉浦智子, 他
  • Organizer: 第5回トランスポーター研究会
  • Place of Presentation: 東京医科大学病院臨床講堂(東京都)(招待講演)
• [Presentation] Adaptor protein PDZK1 affects drug absorption by regulating multiple small intestinal transporters (2010)
  • Author(s): Tomoko Sugiura, et al.
  • Organizer: 2010 FIP PSWC/AAPS
  • Place of Presentation: Morial Convention Center (New Orleans)
• [Book] 細胞工学Vol.31(5)【メタボロミクスによるトランスポーター機能の探索】 (2012)
  • Author(s): 杉浦智子、加藤将夫
  • Total Pages: 625
  • Publisher: 株式会社学研メディカル秀潤社
• [Book] 低分子量GTP結合タンパク質Rab8によるSLCトランスポーターを介した消化管吸収制御 (2011)
  • Author(s): 杉浦智子、加藤将夫
  • Publisher: 株式会社メディカルドゥ
• [Book] 遺伝子欠損マウスのメタボローム解析によるOCTN1(SLC22A4)の生体内機能の解明 (2011)
  • Author(s): 清水卓也、杉浦智子、加藤将夫
  • Publisher: 株式会社メディカルドゥ
• [Book] 遺伝子医学MOOK(19)(低分子量GTP結合タンパク質Rab8によるSLCトランスポーターを介した消化管吸収制御) (2011)
  • Author(s): 杉浦智子、加藤将夫(金井好克編集)
  • Publisher: 株式会社 メディカル ドゥ
• [Book] 遺伝子医学MOOK(19)(遺伝子欠損マウスのメタボローム解析によるOCTN1(SLC22A4)の生体内機能の解明) (2011)
  • Author(s): 清水卓也、杉浦智子、加藤将夫(金井好克編集)
  • Publisher: 株式会社 メディカル ドゥ
• [Book] 有機カチオントランスポーターOCTN1/SLC22A4によるエルゴチオネイン輸送ビタミン・バイオファクターのトランスポーター (2010)
  • Author(s): 杉浦智子、加藤将夫
• [Remarks]
  • URL: http://www.p.kanazawa-u.ac.jp/~bunyaku/