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
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.015768.
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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.
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↵1 Current affiliation: Genentech, Inc., South San Francisco, California.
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↵2 Current affiliation: Roche Pharmaceuticals, Nutley, New Jersey.
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↵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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