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Prediction of Oral Absorption of Anionic Drugs that are Absorbed by the Monocarboxylic Acid Transport System

Research Project

Project/Area Number 11672216
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionKitasato University

Principal Investigator

ITOH Tomoo  Kitasato University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (30223168)

Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsMonocarboxylic Acid / Transporter / Oral Absorption / Caco-2 cells / Penicillins / モノカルボル酸
Research Abstract

Transcellular transport of carbenicillin (CBPC) and caridacillin (CIPC) through Caco-2 cell monolayer in the apical to basal direction was measured. CBPC is used pareterally because of poor absorption from the intestine, whereas CIPC is a prodrug of CBPC and is orally administered. Caco-2 cells were cultured on Transwell and the transport was measured at apical pH=6.0 and basal pH=7.4. Permeability of CIPC through Caco-2 cell monolayer was ca. 40-fold greater than that of CBPC, indicating that improved absorption of CIPC is due to much faster transport through the intestinal epithelial cells. Moreover, it was shown that CIPC, not CBPC, was transported by the monocarboxylic acid transport system that is located at the epithelial cells. It is probably true that modification of chemical structure from CBPC to CIPC resulted in much greater affinity to the transport system, which in turn resulted in greater absorption of the prodrug.
Transport of cloxacillin (MCIPC), dicloxacillin (MDIPC), phenethicillin (PEPC), phenoxymethylpenicillin (PCV) and propicillin (PPPC) through Caco-2 cell monolayer was measured. Permeability of these drugs ranged from 0.8 to 1.0 x 10^<-6> cm/s. If we assume that these drugs are absorbed only by passive diffusion, extent of absorption after oral administration should be 10-20% of the dose (S.Chong et al., Pharm.Res.13 : 120-123, 1996). However, extent of oral absorption of these drugs in humans is 45-86%, which is much greater than that predicted assuming passive diffusion. The results suggest that a transport system, most probably the monocarboxylic acid transport system, is involved in the absorption of these drugs since these drugs have a carboxylic acid moiety and exist as mono-anion at physiological pH.Moreover, in our previous study, it was demonstrated that these drugs have affinity to the monocarboxylic acid transport system.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (6 results)

All Other

All Publications (6 results)

  • [Publications] T.Itoh,K.Ono,K.Koido,Y-H.Li,H.Yamada: "Stereoselectivity of the folate transporter"Chirality. 13. 164-169 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Li YH, Tanno M, Itoh T, Yamada H.: "Role of the monocarboxylic acid transport system in the intestinal absorption of an orally active β-lactam prodrug : Caridacillin as a model."Int.J.Pharmaceut. 191. 151-159 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Li YH, Ito K, Tsuda Y, Kohda R, Yamada H, Itoh T.: "Mechanism of intestinal absorption of of an orally active β-lactam prodrug : Uptake and transport of caridacillin in Caco-2 cells."J.Pharmacol.Exp.Ther.. 290. 958-964 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Itoh T, Ono K, Koido K, Li YH, Yamada H.: "Stereoselectivity of the folate transporter in rabbit small intestine : Studies with amethopterin enantiomers."Chirality. 13. 164-169 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Itoh,K.Ono,K.Koido,Y-H.Li,H.Yamada: "Stereoselectivity of the folate transporter"Chirality. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y-H. Li, K. Ito, Y. Tsuda, R. Kohda, H. Yamada and T. Itoh: "Mechanism of intestinal absorption of an orally active β-lactam"J. Pharmacol. Exp. Ther.. 290(3). 958-964 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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