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Research ArticleArticle

In Vivo Assessment of the Impact of Efflux Transporter on Oral Drug Absorption Using Portal Vein–Cannulated Rats

Yoshiki Matsuda, Yoshihiro Konno, Takashi Hashimoto, Mika Nagai, Takayuki Taguchi, Masahiro Satsukawa and Shinji Yamashita
Drug Metabolism and Disposition August 2013, 41 (8) 1514-1521; DOI: https://doi.org/10.1124/dmd.113.051680
Yoshiki Matsuda
Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (Y.M., Y.K., T.H., M.N., T.T., M.S.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.)
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Yoshihiro Konno
Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (Y.M., Y.K., T.H., M.N., T.T., M.S.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.)
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Takashi Hashimoto
Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (Y.M., Y.K., T.H., M.N., T.T., M.S.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.)
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Mika Nagai
Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (Y.M., Y.K., T.H., M.N., T.T., M.S.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.)
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Takayuki Taguchi
Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (Y.M., Y.K., T.H., M.N., T.T., M.S.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.)
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Masahiro Satsukawa
Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (Y.M., Y.K., T.H., M.N., T.T., M.S.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.)
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Shinji Yamashita
Pharmacokinetics and Safety Research Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan (Y.M., Y.K., T.H., M.N., T.T., M.S.); and Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan (S.Y.)
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Abstract

The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs—fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)—were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein–cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein–cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein–cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.

Footnotes

    • Received February 25, 2013.
    • Accepted May 16, 2013.
  • dx.doi.org/10.1124/dmd.113.051680.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (8)
Drug Metabolism and Disposition
Vol. 41, Issue 8
1 Aug 2013
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Research ArticleArticle

Assessment of the Impact of Intestinal Efflux Transporter

Yoshiki Matsuda, Yoshihiro Konno, Takashi Hashimoto, Mika Nagai, Takayuki Taguchi, Masahiro Satsukawa and Shinji Yamashita
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1514-1521; DOI: https://doi.org/10.1124/dmd.113.051680

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Research ArticleArticle

Assessment of the Impact of Intestinal Efflux Transporter

Yoshiki Matsuda, Yoshihiro Konno, Takashi Hashimoto, Mika Nagai, Takayuki Taguchi, Masahiro Satsukawa and Shinji Yamashita
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1514-1521; DOI: https://doi.org/10.1124/dmd.113.051680
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