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Research ArticleArticle

In Vitro Characterization of Sarizotan Metabolism: Hepatic Clearance, Identification and Characterization of Metabolites, Drug-Metabolizing Enzyme Identification, and Evaluation of Cytochrome P450 Inhibition

Dieter Gallemann, Elmar Wimmer, Constance C. Höfer, Achim Freisleben, Markus Fluck, Bernhard Ladstetter and Hugues Dolgos
Drug Metabolism and Disposition June 2010, 38 (6) 905-916; DOI: https://doi.org/10.1124/dmd.109.029835
Dieter Gallemann
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Elmar Wimmer
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Constance C. Höfer
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Achim Freisleben
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Markus Fluck
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Bernhard Ladstetter
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Hugues Dolgos
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Abstract

In vitro biotransformation studies of sarizotan using human liver microsomes (HLM) showed aromatic and aliphatic monohydroxylation and dealkylation. Recombinant cytochromes P450 (P450) together with P450-selective inhibitors in HLM/hepatocyte cultures were used to evaluate the relative contribution of different P450s and revealed major involvement of CYP3A4, CYP2C9, CYP2C8, and CYP1A2 in sarizotan metabolism. The apparent Km, u and Vmax of sarizotan clearance, as investigated in HLM, were 9 μM and 3280 pmol/mg/min, predicting in vivo hepatic clearance of 0.94 l/h, which indicates that sarizotan is a low-clearance compound in humans and suggests nonsaturable metabolism at the targeted plasma concentration (≤1 μM). This finding is confirmed by the reported human clearance (CL/F of 3.6–4.4 l/h) and by the dose-linear area under the curve increase observed with doses up to 25 mg. The inhibitory effect of sarizotan toward six major P450s was evaluated using P450-specific marker reactions in pooled HLM. Ki, u values of sarizotan against CYP2C8, CYP2C19, and CYP3A4 were >10 μM, whereas those against CYP2D6 and CYP1A2 were 0.43 and 8.7 μM, respectively. Based on the estimates of sarizotan concentrations at the enzyme active sites, no clinically significant drug-drug interactions (DDIs) due to P450 inhibition are expected. This result has been confirmed in human DDI studies in which no inhibition of five major P450s was observed in terms of marker metabolite formation.

Footnotes

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

    doi:10.1124/dmd.109.029835.

  • ↵Graphic The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    SZ
    sarizotan
    AUC
    area under the curve
    Cmax
    maximum plasma concentration
    tmax
    time of maximum plasma concentration
    NCE
    new chemical entity
    P450
    cytochrome P450
    DDI
    drug-drug interaction
    PK
    pharmacokinetic(s)
    HLM
    human liver microsome(s)
    ABT
    aminobenzotriazole
    EMD 148107
    (−)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-6-hydroxychromane, dihydrochloride
    EMD 329989
    2R,4R/S)-2-({[5-(4-fluorophenyl)-pyridine-3-ylmethyl]-amino}-methyl)-chromane-4-ol
    EMD 50929
    3-(4-fluorophenyl)-pyridine-5-carbonic acid
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    HPLC
    high-pressure liquid chromatography
    RT
    retention time
    Ki, u
    inhibitory constant considering fu in microsomal incubations
    Km, u
    unbound Michaelis-Menten constant.

  • Received August 21, 2009.
  • Accepted March 10, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (6)
Drug Metabolism and Disposition
Vol. 38, Issue 6
1 Jun 2010
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Research ArticleArticle

In Vitro Characterization of Sarizotan Metabolism: Hepatic Clearance, Identification and Characterization of Metabolites, Drug-Metabolizing Enzyme Identification, and Evaluation of Cytochrome P450 Inhibition

Dieter Gallemann, Elmar Wimmer, Constance C. Höfer, Achim Freisleben, Markus Fluck, Bernhard Ladstetter and Hugues Dolgos
Drug Metabolism and Disposition June 1, 2010, 38 (6) 905-916; DOI: https://doi.org/10.1124/dmd.109.029835

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Research ArticleArticle

In Vitro Characterization of Sarizotan Metabolism: Hepatic Clearance, Identification and Characterization of Metabolites, Drug-Metabolizing Enzyme Identification, and Evaluation of Cytochrome P450 Inhibition

Dieter Gallemann, Elmar Wimmer, Constance C. Höfer, Achim Freisleben, Markus Fluck, Bernhard Ladstetter and Hugues Dolgos
Drug Metabolism and Disposition June 1, 2010, 38 (6) 905-916; DOI: https://doi.org/10.1124/dmd.109.029835
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