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Research ArticleArticle

Application of Liquid Chromatography/Mass Spectrometry in Accelerating the Identification of Human Liver Cytochrome P450 Isoforms Involved in the Metabolism of Iloperidone

A. E. Mutlib and J. T. Klein
Journal of Pharmacology and Experimental Therapeutics September 1998, 286 (3) 1285-1293;
A. E. Mutlib
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J. T. Klein
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Abstract

Iloperidone, [1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, 1, is currently undergoing clinical trials as a potential antipsychotic agent. The metabolism of iloperidone was studied in human liver microsomes to define the metabolic pathways and to identify the cytochrome P450 (CYP) isoforms responsible for the formation of major iloperidone metabolites. Iloperidone was extensively metabolized in vitrovia hydroxylation, reduction andO-demethylation to produce 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone,4; 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzene methanol, 3, and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone,2, respectively, in decreasing order of abundance. The majorin vitro metabolite, 4, present in trace quantities in urine, was postulated to be either eliminated in bile as a conjugate or further metabolized to a phenol, 4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-piperidin1-yl]propoxy]-3-methoxyphenol,5. The formation of the three major in vitrometabolites 2, 3 and 4 was NADPH dependent. The major circulating and urinary metabolite in humans dosed with 1 was metabolite 3. The mean apparentKm and Vmaxfor formation of 2 by human liver microsomes was 7.4 ± 3.0 μM and 0.0343 ± 0.0134 nmol min−1mg−1, respectively. The mean apparentKm and Vmaxfor 3 was 101.2 ± 34.7 μM and 0.1414 ± 0.0346 nmol min−1 mg−1, respectively. The mean apparent KmandVmax for 4was 39.7 ± 10.8 μM and 0.1372 ± 0.056 nmol min−1 mg−1, respectively. The CYP isoenzymes responsible for the formation of metabolites 2, 3 and 4 were determined by using selective chemical inhibitors and by correlation studies. Metabolites 2 and 4 were formed by CYP3A4 and by the polymorphic CYP2D6 respectively. Metabolite 3 is postulated to be produced mainly by a cytosolic enzyme(s), although CYP3A, CYP1A2 and CYP2E1 isozymes were shown to be involved in its formation as well. The power of liquid chromatography/mass spectrometry in greatly accelerating the process of identifying the human liver CYP isoforms involved in the metabolism of iloperidone was demonstrated in this study. Liquid chromatography/mass spectrometry was used in the initial studies to confirm the identities of the metabolites. This was followed by accurate and reliable quantitation of individual metabolites present in biological extracts by operating the mass spectrometer in the selected ion monitoring mode.

Footnotes

  • Send reprint requests to: Dr. A. E. Mutlib, DuPont Pharmaceuticals Company, Stine Haskell Research Center, Bldg. 110, P.O. Box 30, Elkton Road, Newark, DE 19714-0030.

  • Abbreviations:
    CYP
    cytochrome P450
    LC/MS
    liquid chromatography/mass spectrometry
    NMR
    nuclear magnetic resonance
    HPLC
    high performance liquid chromatography
    SIM
    selected ion monitoring
    • Received February 16, 1998.
    • Accepted May 11, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 3
1 Sep 1998
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Research ArticleArticle

Application of Liquid Chromatography/Mass Spectrometry in Accelerating the Identification of Human Liver Cytochrome P450 Isoforms Involved in the Metabolism of Iloperidone

A. E. Mutlib and J. T. Klein
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1285-1293;

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Research ArticleArticle

Application of Liquid Chromatography/Mass Spectrometry in Accelerating the Identification of Human Liver Cytochrome P450 Isoforms Involved in the Metabolism of Iloperidone

A. E. Mutlib and J. T. Klein
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1285-1293;
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