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Research ArticleArticle

Prediction of Relative In Vivo Metabolite Exposure from In Vitro Data Using Two Model Drugs: Dextromethorphan and Omeprazole

Justin D. Lutz and Nina Isoherranen
Drug Metabolism and Disposition January 2012, 40 (1) 159-168; DOI: https://doi.org/10.1124/dmd.111.042200
Justin D. Lutz
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Nina Isoherranen
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Abstract

Metabolites can have pharmacological or toxicological effects, inhibit metabolic enzymes, and be used as probes of drug-drug interactions or specific cytochrome P450 (P450) phenotypes. Thus, better understanding and prediction methods are needed to characterize metabolite exposures in vivo. This study aimed to test whether in vitro data could be used to predict and rationalize in vivo metabolite exposures using two model drugs and P450 probes: dextromethorphan and omeprazole with their primary metabolites dextrorphan, 5-hydroxyomeprazole (5OH-omeprazole), and omeprazole sulfone. Relative metabolite exposures were predicted using metabolite formation and elimination clearances. For dextrorphan, the formation clearances of dextrorphan glucuronide and 3-hydroxymorphinan from dextrorphan in human liver microsomes were used to predict metabolite (dextrorphan) clearance. For 5OH-omeprazole and omeprazole sulfone, the depletion rates of the metabolites in human hepatocytes were used to predict metabolite clearance. Dextrorphan/dextromethorphan in vivo metabolite/parent area under the plasma concentration versus time curve ratio (AUCm/AUCp) was overpredicted by 2.1-fold, whereas 5OH-omeprazole/omeprazole and omeprazole sulfone/omeprazole were predicted within 0.75- and 1.1-fold, respectively. The effect of inhibition or induction of the metabolite's formation and elimination on the AUCm/AUCp ratio was simulated. The simulations showed that unless metabolite clearance pathways are characterized, interpretation of the metabolic ratios is exceedingly difficult. This study shows that relative in vivo metabolite exposure can be predicted from in vitro data and characterization of secondary metabolism of probe metabolites is critical for interpretation of phenotypic data.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant P01-GM32165-02].

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

    http://dx.doi.org/10.1124/dmd.111.042200.

  • ABBREVIATIONS:

    R-130964
    (3Z)-3-(carboxymethylene)-α-(2-chlorophenyl)-4-mercapto-1-piperidineacetic acid 1-methyl ester
    5-HT
    5-hydroxytryptamine
    P450
    cytochrome P450
    5OH-omeparazole
    5-hydroxyomeprazole
    AUC
    area under the plasma concentration versus time curve
    AUCm/AUCp
    metabolite/parent area under the plasma concentration versus time curve ratio
    BSA
    bovine serum albumin
    Cl
    clearance
    Clf
    metabolite formation clearance
    Cli
    intrinsic clearance
    Cli,dep
    intrinsic depletion clearance
    Cli,f
    metabolite intrinsic formation clearance
    Cli,u
    intrinsic unbound clearance
    Cm/Cp
    metabolite/parent plasma concentration ratio
    E
    enzyme
    fu
    fraction unbound
    fu,mic
    microsomal fraction unbound
    HLM
    human liver microsomes
    KPi
    potassium phosphate
    M
    metabolite
    MP
    microsomal protein
    P
    parent
    rUGT
    recombinantly expressed uridine diphosphate glucuronosyltransferase
    UDPGA
    uridine diphosphate glucuronic acid
    UGT
    uridine diphosphate glucuronosyltransferase
    Vmax
    maximum velocity
    HPLC
    high-performance liquid chromatography
    ADH
    alcohol dehydrogenase.

  • Received August 5, 2011.
  • Accepted October 18, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

DEXTROMETHORPHAN AND OMEPRAZOLE METABOLITE/PARENT AUC RATIOS

Justin D. Lutz and Nina Isoherranen
Drug Metabolism and Disposition January 1, 2012, 40 (1) 159-168; DOI: https://doi.org/10.1124/dmd.111.042200

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Research ArticleArticle

DEXTROMETHORPHAN AND OMEPRAZOLE METABOLITE/PARENT AUC RATIOS

Justin D. Lutz and Nina Isoherranen
Drug Metabolism and Disposition January 1, 2012, 40 (1) 159-168; DOI: https://doi.org/10.1124/dmd.111.042200
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