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Drug Metabolism & Disposition

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OtherShort Communication

Oseltamivir (Tamiflu) Efflux Transport at the Blood-Brain Barrier via P-Glycoprotein

Kaori Morimoto, Masanori Nakakariya, Yoshiyuki Shirasaka, Chihaya Kakinuma, Takuya Fujita, Ikumi Tamai and Takuo Ogihara
Drug Metabolism and Disposition January 2008, 36 (1) 6-9; DOI: https://doi.org/10.1124/dmd.107.017699
Kaori Morimoto
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Masanori Nakakariya
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Yoshiyuki Shirasaka
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Chihaya Kakinuma
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Takuya Fujita
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Ikumi Tamai
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Takuo Ogihara
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Abstract

Oseltamivir (Tamiflu, Roche, Nutley, NJ), an ester-type prodrug of the anti-influenza drug Ro 64–0802 (oseltamivir carboxylate), has been reported to be associated with neuropsychiatric side effects, which are likely to be caused by distribution of oseltamivir and/or its metabolite into the central nervous system. Enhanced toxicity and brain distribution of oseltamivir in unweaned rats led us to hypothesize that the low level of distribution of oseltamivir and/or Ro 64–0802 in adult brain was caused by the presence of a specific efflux transporter at the blood-brain barrier. We examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64–0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance protein 1 P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice. The permeability of oseltamivir in the basal-to-apical direction was significantly greater than that in the opposite direction. The directional transport disappeared on addition of cyclosporin A, a P-gp inhibitor. The brain distribution of oseltamivir was increased in mdr1a/1b knockout mice compared with wild-type mice. In contrast, negligible transport of Ro 64–0802 by P-gp was observed in both in vitro and in vivo studies. These results show that oseltamivir, but not Ro 64–0802, is a substrate of P-gp. Accordingly, low levels of P-gp activity or drug-drug interactions at P-gp may lead to enhanced brain accumulation of oseltamivir, and this may in turn account for the central nervous system effects of oseltamivir observed in some patients.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.017699.

  • ABBREVIATIONS: CNS, central nervous system; BBB, blood-brain barrier; P-gp, P-glycoprotein; HPLC, high-performance liquid chromatography.

    • Received July 20, 2007.
    • Accepted October 11, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (1)
Drug Metabolism and Disposition
Vol. 36, Issue 1
1 Jan 2008
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OtherShort Communication

Oseltamivir (Tamiflu) Efflux Transport at the Blood-Brain Barrier via P-Glycoprotein

Kaori Morimoto, Masanori Nakakariya, Yoshiyuki Shirasaka, Chihaya Kakinuma, Takuya Fujita, Ikumi Tamai and Takuo Ogihara
Drug Metabolism and Disposition January 1, 2008, 36 (1) 6-9; DOI: https://doi.org/10.1124/dmd.107.017699

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OtherShort Communication

Oseltamivir (Tamiflu) Efflux Transport at the Blood-Brain Barrier via P-Glycoprotein

Kaori Morimoto, Masanori Nakakariya, Yoshiyuki Shirasaka, Chihaya Kakinuma, Takuya Fujita, Ikumi Tamai and Takuo Ogihara
Drug Metabolism and Disposition January 1, 2008, 36 (1) 6-9; DOI: https://doi.org/10.1124/dmd.107.017699
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