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Research ArticleArticle

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1A Receptor Occupancy in Rats

Harvey Wong, Randy C. Dockens, Lori Pajor, Suresh Yeola, James E. Grace Jr., Arlene D. Stark, Rebecca A. Taub, Frank D. Yocca, Robert C. Zaczek and Yu-Wen Li
Drug Metabolism and Disposition August 2007, 35 (8) 1387-1392; DOI: https://doi.org/10.1124/dmd.107.015768
Harvey Wong
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Randy C. Dockens
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Lori Pajor
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Suresh Yeola
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James E. Grace Jr.
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Arlene D. Stark
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Rebecca A. Taub
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Frank D. Yocca
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Robert C. Zaczek
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Yu-Wen Li
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Abstract

The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 ± 3.5 ml/min/kg), volume of distribution (2.6 ± 0.3 l/kg), and half-life (1.2 ± 0.2 h) of 6-OH-buspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT)1A receptor occupancy in a concentration-dependent manner with EC50 values of 1.0 ± 0.3 and 0.38 ± 0.06 μMinthe dorsal raphe and 4.0 ± 0.6 and 1.5 ± 0.3 μM in the hippocampus, respectively. Both compounds appeared to be ∼4-fold more potent in occupying presynaptic 5-HT1A receptors in the dorsal raphe than the postsynaptic receptors in the hippocampus. Oral dosing of buspirone in rats resulted in exposures (area under the concentration-time profile) of 6-OH-buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP), another major metabolite of buspirone, that were ∼12 (6-OH-buspirone)- and 49 (1-PP)-fold higher than the exposure of the parent compound. As a whole, these preclinical data suggest that 6-OH-buspirone probably contributes to the clinical efficacy of buspirone as an anxiolytic agent.

Footnotes

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

  • doi:10.1124/dmd.107.015768.

  • ABBREVIATIONS: 5HT, 5-hydroxytryptamine; OH, hydroxy; 1-PP, 1-(2-pyrimidinyl)-piperazine; LC/MS/MS, liquid chromatography-tandem mass spectrometry; WAY-100635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; AUC, area under the plasma-concentration time profile; EMD 128 130, sarizotan.

  • ↵1 Current affiliation: Genentech, Inc., South San Francisco, California.

  • ↵2 Current affiliation: Roche Pharmaceuticals, Nutley, New Jersey.

  • ↵3 Current affiliation: AstraZeneca Pharmaceuticals, Wilmington, Delaware.

    • Received March 16, 2007.
    • Accepted May 8, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (8)
Drug Metabolism and Disposition
Vol. 35, Issue 8
1 Aug 2007
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Research ArticleArticle

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1A Receptor Occupancy in Rats

Harvey Wong, Randy C. Dockens, Lori Pajor, Suresh Yeola, James E. Grace, Arlene D. Stark, Rebecca A. Taub, Frank D. Yocca, Robert C. Zaczek and Yu-Wen Li
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1387-1392; DOI: https://doi.org/10.1124/dmd.107.015768

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Research ArticleArticle

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1A Receptor Occupancy in Rats

Harvey Wong, Randy C. Dockens, Lori Pajor, Suresh Yeola, James E. Grace, Arlene D. Stark, Rebecca A. Taub, Frank D. Yocca, Robert C. Zaczek and Yu-Wen Li
Drug Metabolism and Disposition August 1, 2007, 35 (8) 1387-1392; DOI: https://doi.org/10.1124/dmd.107.015768
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