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Research ArticleArticle

Limited Brain Distribution of [3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (Ro 64-0802), a Pharmacologically Active Form of Oseltamivir, by Active Efflux across the Blood-Brain Barrier Mediated by Organic Anion Transporter 3 (Oat3/Slc22a8) and Multidrug Resistance-Associated Protein 4 (Mrp4/Abcc4)

Atsushi Ose, Mototsugu Ito, Hiroyuki Kusuhara, Kenzo Yamatsugu, Motomu Kanai, Masakatsu Shibasaki, Masakiyo Hosokawa, John D. Schuetz and Yuichi Sugiyama
Drug Metabolism and Disposition February 2009, 37 (2) 315-321; DOI: https://doi.org/10.1124/dmd.108.024018
Atsushi Ose
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Mototsugu Ito
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Hiroyuki Kusuhara
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Kenzo Yamatsugu
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Motomu Kanai
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Masakatsu Shibasaki
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Masakiyo Hosokawa
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John D. Schuetz
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Yuichi Sugiyama
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Abstract

[3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802) is a pharmacologically active form of the anti-influenza virus drug oseltamivir. Abnormal behavior is a suspected adverse effect of oseltamivir on the central nervous system. This study focused on the transport mechanisms of Ro 64-0802 across the blood-brain barrier (BBB). Ro 64-0802 was found to be a substrate of organic anion transporter 3 (OAT3/SLC22A8) and multidrug resistance-associated protein 4 (MRP4/ABCC4). Human embryonic kidney 293 cells expressing OAT3 exhibited a greater intracellular accumulation of Ro 64-0802 than mock-transfected cells (15 versus 1.2 μl/mg protein/10 min, respectively). The efflux of Ro 64-0802 was 3-fold greater when MRP4 was expressed in MDCKII cells and was significantly inhibited by indomethacin. After its microinjection into the cerebrum, the amount of Ro 64-0802 in brain was significantly greater in both Oat3–/– mice and Mrp4–/– mice compared with the corresponding wild-type mice (0.36 versus 0.080 and 0.32 versus 0.060 nmol at 120 min after injection, respectively). The brain/plasma concentration ratio (Kp,brain) of Ro 64-0802, determined in wild-type mice after subcutaneous continuous infusion for 24 h, was close to the capillary volume (approximately 10 μl/g brain). Although the Kp,brain of Ro 64-0802 was unchanged in Oat3–/– mice, it was significantly greater in Mrp4–/– mice (41 μl/g of brain). These results suggest that Ro 64-0802 can cross the BBB from the blood, but its brain distribution is limited by its active efflux by Mrp4 and Oat3 across the BBB. The transporter responsible for the brain uptake of Ro 64-0802 remains unknown, but Oat3 is a candidate transporter.

Footnotes

  • This work supported in part by a grant-in-aid for Scientific Research (A) [Grant 20249008] and Scientific Research (B) [Grant 20390046] from the Ministry of Education, Culture, Sports, Science and Technology.

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

  • doi:10.1124/dmd.108.024018.

  • ABBREVIATIONS: Ro 64-0802, [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate; BBB, blood-brain barrier; CES1A1, carboxylesterase 1A1; P-gp, P-glycoprotein; Oat/OAT, organic anion transporter; Mrp/MRP, multidrug resistance-associated protein; HEK, human embryonic kidney; MDCK, Madin-Darby canine kidney; LC, liquid chromatography; MS, mass spectrometry; GFP, green fluorescent protein; ANOVA, analysis of variance; PCR, polymerase chain reaction; Mdr, multidrug resistance; Bcrp, breast cancer resistance protein; Oatp, organic anion transporter peptide.

    • Received August 18, 2008.
    • Accepted November 20, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (2)
Drug Metabolism and Disposition
Vol. 37, Issue 2
1 Feb 2009
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Research ArticleArticle

Limited Brain Distribution of [3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (Ro 64-0802), a Pharmacologically Active Form of Oseltamivir, by Active Efflux across the Blood-Brain Barrier Mediated by Organic Anion Transporter 3 (Oat3/Slc22a8) and Multidrug Resistance-Associated Protein 4 (Mrp4/Abcc4)

Atsushi Ose, Mototsugu Ito, Hiroyuki Kusuhara, Kenzo Yamatsugu, Motomu Kanai, Masakatsu Shibasaki, Masakiyo Hosokawa, John D. Schuetz and Yuichi Sugiyama
Drug Metabolism and Disposition February 1, 2009, 37 (2) 315-321; DOI: https://doi.org/10.1124/dmd.108.024018

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Research ArticleArticle

Limited Brain Distribution of [3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (Ro 64-0802), a Pharmacologically Active Form of Oseltamivir, by Active Efflux across the Blood-Brain Barrier Mediated by Organic Anion Transporter 3 (Oat3/Slc22a8) and Multidrug Resistance-Associated Protein 4 (Mrp4/Abcc4)

Atsushi Ose, Mototsugu Ito, Hiroyuki Kusuhara, Kenzo Yamatsugu, Motomu Kanai, Masakatsu Shibasaki, Masakiyo Hosokawa, John D. Schuetz and Yuichi Sugiyama
Drug Metabolism and Disposition February 1, 2009, 37 (2) 315-321; DOI: https://doi.org/10.1124/dmd.108.024018
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