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Research ArticleArticle

CYTOCHROME P450 3A-MEDIATED METABOLISM OF BUSPIRONE IN HUMAN LIVER MICROSOMES

Mingshe Zhu, Weiping Zhao, Humberto Jimenez, Donglu Zhang, Suresh Yeola, Renke Dai, Nimish Vachharajani and James Mitroka
Drug Metabolism and Disposition April 2005, 33 (4) 500-507; DOI: https://doi.org/10.1124/dmd.104.000836
Mingshe Zhu
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Weiping Zhao
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Humberto Jimenez
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Donglu Zhang
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Suresh Yeola
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Renke Dai
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Nimish Vachharajani
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James Mitroka
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Abstract

This study was carried out to determine the metabolic pathways of buspirone and cytochrome P450 (P450) isoform(s) responsible for buspirone metabolism in human liver microsomes (HLMs). Buspirone mainly underwent N-dealkylation to 1-pyrimidinylpiperazine (1-PP), N-oxidation on the piperazine ring to buspirone N-oxide (Bu N-oxide), and hydroxylation to 3′-hydroxybuspirone (3′-OH-Bu), 5-hydroxybuspirone (5-OH-Bu), and 6′-hydroxybuspirone (6′-OH-Bu) in HLMs. The apparent Km values for buspirone metabolite formation in pooled HLMs were 8.7 (1-PP), 34.0 (Bu N-oxide), 4.3 (3′-OH-Bu), 11.4/514 (5-OH-Bu), and 8.8 μM (6′-OH-Bu). CYP3A inhibitor ketoconazole (1 μM) completely inhibited the formation of all major metabolites in HLMs (0-16% of control), whereas the chemical inhibitor selective to other P450 isoforms had little or no inhibitory effect. Recombinant CYP3A4, CYP3A5, and CYP2D6 exhibited buspirone oxidation activities among nine P450 isoforms tested. The overall metabolism rate of 5 μM buspirone by CYP3A4 was 18-fold greater than that by CYP2D6 and 35-fold greater than that by CYP3A5. In a panel of HLMs from 16 donors, buspirone metabolism correlated well CYP3A activity (r2 = 0.85-0.96, ρ < 0.0005), but not the activities of other P450 isoforms. The metabolism rates of buspirone in CYP2D6 poor-metabolizer genotype HLMs were comparable to those in pooled HLMs. Taken together, these data suggest that CYP3A, mostly likely CYP3A4, is primarily responsible for the metabolism of buspirone in HLMs.

Footnotes

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

  • doi:10.1124/dmd.104.000836.

  • ABBREVIATIONS: FDA, Food and Drug Administration; P450, cytochrome P450; HLM, human liver microsome; 1-PP, 1-pyrimidinylpiperazine; 3′-OH-Bu, 3′-hydroxybuspirone; 5-OH-Bu, 5-hydroxybuspirone; 6′-OH-Bu, 6′-hydroxybuspirone; Bu N-oxide, buspirone N-oxide; 5-OH-1-PP, 5-hydroxy-1-pyrimidinylpiperazine; 5,6′-di-OH-Bu, 5,6′-dihydroxybuspirone; Oxa-Bu, 3-oxo-N-[4-[-(2-pyrimidinyl)-1-piperazinyl]butyl]-2-oxaspiro-[4,4]nonane-1-carboxamide; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; LC/MS/MS, liquid chromatography/tanden mass spectrometry; MH+, protonated molecular ion; MSC, microplate scintillation counter; RFD, radio flow detector; Km, Michaelis content; Vmax, maximal initial reaction velocity; CLint, intrinsic clearance (Km/Vmax); AUC, area under the plasma concentration-time curve; Cmax, maximum plasma concentration.

    • Received June 3, 2004.
    • Accepted January 3, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (4)
Drug Metabolism and Disposition
Vol. 33, Issue 4
1 Apr 2005
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Research ArticleArticle

CYTOCHROME P450 3A-MEDIATED METABOLISM OF BUSPIRONE IN HUMAN LIVER MICROSOMES

Mingshe Zhu, Weiping Zhao, Humberto Jimenez, Donglu Zhang, Suresh Yeola, Renke Dai, Nimish Vachharajani and James Mitroka
Drug Metabolism and Disposition April 1, 2005, 33 (4) 500-507; DOI: https://doi.org/10.1124/dmd.104.000836

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Research ArticleArticle

CYTOCHROME P450 3A-MEDIATED METABOLISM OF BUSPIRONE IN HUMAN LIVER MICROSOMES

Mingshe Zhu, Weiping Zhao, Humberto Jimenez, Donglu Zhang, Suresh Yeola, Renke Dai, Nimish Vachharajani and James Mitroka
Drug Metabolism and Disposition April 1, 2005, 33 (4) 500-507; DOI: https://doi.org/10.1124/dmd.104.000836
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