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Research ArticleArticle

SATURABLE DISTRIBUTION OF TACRINE INTO THE STRIATAL EXTRACELLULAR FLUID OF THE RAT: EVIDENCE OF INVOLVEMENT OF MULTIPLE ORGANIC CATION TRANSPORTERS IN THE TRANSPORT

Jong-Hyuk Sung, Kyung-Ha Yu, Jin-Sun Park, Takashi Tsuruo, Dae-Duk Kim, Chang-Koo Shim and Suk-Jae Chung
Drug Metabolism and Disposition March 2005, 33 (3) 440-448; DOI: https://doi.org/10.1124/dmd.104.002220
Jong-Hyuk Sung
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Kyung-Ha Yu
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Jin-Sun Park
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Takashi Tsuruo
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Dae-Duk Kim
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Chang-Koo Shim
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Suk-Jae Chung
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Abstract

The kinetics and mechanism by which tacrine is distributed in the rat brain were examined. Tacrine levels in plasma and striatal extracellular fluid were used to evaluate the pharmacokinetics of this process. The KD,brain was decreased with the dose for tacrine, indicating that the distribution to the brain is saturable. The uptake of organic cations such as choline, 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), and carnitine was inhibited by the addition of tacrine to cultures of mouse immortalized brain capillary endothelial cells. In addition, the apical to basal transport and basal to apical transport of tacrine were inhibited by the addition of organic cations to cultures of LLC-PK1 cells, suggesting that tacrine transport across the blood-brain barrier (BBB) is mediated by organic cation transport system(s). Consistent with the in vitro results, a standard reverse transcription-polymerase chain reaction procedure was able to amplify the message of mOCT2 and mOCTN2, but not mOCT1, in MBEC4 (mouse brain microvessel endothelial cell line 4) cells. Similarly, mRNAs for rOCT2 and rOCTN2 were present in representative rat brain samples. To determine whether OCT2 and/or OCTN2 transport tacrine, these transporters were cloned and then transfected in SK-HEP1 and HEK 293 cells. The uptake of choline, MPP, and TEA was inhibited by the presence of tacrine in rOCT2-expressing SK-HEP1 cells, whereas the uptake of carnitine was inhibited by the presence of tacrine in rOCTN2-expressing HEK 293 cells. Collectively, these observations suggest that the transport of tacrine across the BBB is mediated, at least in part, by multiple organic cation transport systems in rats.

Footnotes

  • This study was supported, in part, by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (02-PJ2-PG6-DC04-0001).

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

  • doi:10.1124/dmd.104.002220.

  • ABBREVIATIONS: BBB, blood-brain barrier; MPP, 1-methyl-4-phenylpyridinium; TEA, tetraethylammonium; OCT, organic cation transporter; ECF, extracellular fluid; HPLC, high performance liquid chromatography; RT-PCR, reverse transcription-polymerase chain reaction; ANOVA, analysis of variance; r, rat; m, mouse.

    • Received September 9, 2004.
    • Accepted November 12, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (3)
Drug Metabolism and Disposition
Vol. 33, Issue 3
1 Mar 2005
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Research ArticleArticle

SATURABLE DISTRIBUTION OF TACRINE INTO THE STRIATAL EXTRACELLULAR FLUID OF THE RAT: EVIDENCE OF INVOLVEMENT OF MULTIPLE ORGANIC CATION TRANSPORTERS IN THE TRANSPORT

Jong-Hyuk Sung, Kyung-Ha Yu, Jin-Sun Park, Takashi Tsuruo, Dae-Duk Kim, Chang-Koo Shim and Suk-Jae Chung
Drug Metabolism and Disposition March 1, 2005, 33 (3) 440-448; DOI: https://doi.org/10.1124/dmd.104.002220

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Research ArticleArticle

SATURABLE DISTRIBUTION OF TACRINE INTO THE STRIATAL EXTRACELLULAR FLUID OF THE RAT: EVIDENCE OF INVOLVEMENT OF MULTIPLE ORGANIC CATION TRANSPORTERS IN THE TRANSPORT

Jong-Hyuk Sung, Kyung-Ha Yu, Jin-Sun Park, Takashi Tsuruo, Dae-Duk Kim, Chang-Koo Shim and Suk-Jae Chung
Drug Metabolism and Disposition March 1, 2005, 33 (3) 440-448; DOI: https://doi.org/10.1124/dmd.104.002220
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