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Research ArticleArticle

PREDICTION OF CYP2C9-MEDIATED DRUG-DRUG INTERACTIONS: A COMPARISON USING DATA FROM RECOMBINANT ENZYMES AND HUMAN HEPATOCYTES

Dermot F. McGinnity, James Tucker, Steve Trigg and Robert J. Riley
Drug Metabolism and Disposition November 2005, 33 (11) 1700-1707; DOI: https://doi.org/10.1124/dmd.105.005884
Dermot F. McGinnity
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James Tucker
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Steve Trigg
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Robert J. Riley
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Abstract

The IC50 values of 14 drugs were determined in recombinantly expressed CYP2C9 (rCYP2C9) and human hepatocytes and the data used to simulate clinical area under the plasma concentration-time curve (AUC) changes upon coadministration with prototypic CYP2C9 substrates. There was an excellent correlation between IC50, apparent values determined using diclofenac and naproxen as CYP2C9 substrates (r2 = 0.82, p < 0.0001), with values being generally higher in the naproxen assay. After correcting for nonspecific binding, the IC50, unbound values were similar between the assays, for the majority of compounds. Two compounds, amiodarone and benzbromarone, demonstrated substrate-specific differences, activating naproxen O-demethylase to ∼250% of control activity at 1 mM and 1 μM, respectively, while inhibiting diclofenac 4′-hydroxylation with IC50, apparent values of 3 μM and 0.04 μM, respectively. CYP2C9 IC50, apparent values generated in human hepatocytes were systematically higher than those determined with rCYP2C9. After correcting for nonspecific binding, there was an excellent correlation of IC50, unbound values generated in the different milieu (r2 = 0.88, p < 0.0001). The ratio of inhibitor concentration at the entrance to the liver to the inhibition constant ([I]in/Ki) was used to simulate clinical δAUC changes and compared with that observed in vivo. Where [I]in, total/Ki, apparent was used, there were zero false negatives (observed δAUC ≥2, predicted δAUC <2), eight correct assignations, and seven false positives (observed δAUC ≤2, predicted δAUC >2. Where [I]in, unbound/Ki, unbound was used, there was one false negative, 14 correct assignations, and zero false positives. In summary, the data presented here suggest that for CYP2C9 interactions, the use of total liver inhibitor concentrations may indeed avoid false negatives, but more realistic predictions may be achieved using unbound liver inhibitor concentrations and unbound in vitro inhibition parameters.

Footnotes

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

  • doi:10.1124/dmd.105.005884.

  • ABBREVIATIONS: DDI, drug-drug interaction; P450, cytochrome P450; rCYP2C9, recombinant cytochrome P450 2C9; HPLC, high-performance liquid chromatography; fuinc, unbound fraction in incubation; fup, unbound fraction in plasma; RSP, robotic sample processor; [I], inhibitor concentration; [I]av, average systemic plasma concentration after repeated oral administration; [I]max, maximum systemic plasma concentration after repeated oral administration; [I]in, maximum hepatic input concentration; Ki, inhibition constant; AUC, area under the plasma concentration-time curve; fmCYP2C9, fraction of total clearance metabolized by CYP2C9.

    • Received June 1, 2005.
    • Accepted August 3, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (11)
Drug Metabolism and Disposition
Vol. 33, Issue 11
1 Nov 2005
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Research ArticleArticle

PREDICTION OF CYP2C9-MEDIATED DRUG-DRUG INTERACTIONS: A COMPARISON USING DATA FROM RECOMBINANT ENZYMES AND HUMAN HEPATOCYTES

Dermot F. McGinnity, James Tucker, Steve Trigg and Robert J. Riley
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1700-1707; DOI: https://doi.org/10.1124/dmd.105.005884

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Research ArticleArticle

PREDICTION OF CYP2C9-MEDIATED DRUG-DRUG INTERACTIONS: A COMPARISON USING DATA FROM RECOMBINANT ENZYMES AND HUMAN HEPATOCYTES

Dermot F. McGinnity, James Tucker, Steve Trigg and Robert J. Riley
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1700-1707; DOI: https://doi.org/10.1124/dmd.105.005884
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