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Research ArticleArticle

Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. III. In Vitro-in Vivo Correlation with Fluconazole

Chuang Lu, Cicely Berg, Shimoga R. Prakash, Frank W. Lee and Suresh K. Balani
Drug Metabolism and Disposition July 2008, 36 (7) 1261-1266; DOI: https://doi.org/10.1124/dmd.107.019000
Chuang Lu
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Cicely Berg
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Shimoga R. Prakash
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Frank W. Lee
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Suresh K. Balani
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Abstract

Whereas ketoconazole is often used to study the worst-case scenario for clinical pharmacokinetic drug-drug interactions (DDIs) for drugs that are primarily metabolized by CYP3A4, fluconazole is considered to be a moderate inhibitor of CYP3A4, providing assessment of the moderate-case scenario of CYP3A-based DDIs. Fluconazole is also a moderate inhibitor of CYP2C9 and CYP2C19. For predicting clinical DDIs using conventional approaches, determining the in vivo inhibitor concentration at the enzymatic site [I], a critical parameter, is still not practical. In our previous study, a novel method involving hepatocyte suspension in plasma was used to circumvent the need to determine the elusive [I] value. In this study, the CYP1A2, 2C9, 2C19, 2D6, and 3A4 activities remaining in the presence of fluconazole were determined in human hepatocytes suspended in human plasma, covering a range of fluconazole clinical plasma concentrations (Cavg and Cmax). Because the protein-binding effect of fluconazole is expected to be close to that in vivo, the inhibition observed in vitro will be similar to that in vivo. This inhibition information was then applied to the cytochrome P450 (P450) phenotypic data to predict DDIs. Using the available P450 phenotypic information on theophylline, tolbutamide, omeprazole, S-warfarin, phenytoin, cyclosporine, and midazolam and that determined in this study for sirolimus and tacrolimus, we found that the predictions for area under the curve increases for most of these drugs in the presence of fluconazole were remarkably similar (within 35%) to the observed clinical values. This study proves the general applicability of our approach using human hepatocyte incubation in human plasma to predict DDIs.

Footnotes

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

  • doi:10.1124/dmd.107.019000.

  • ABBREVIATIONS: CYP, cytochrome P450; CYP3A4, CYP3A4/5; Pgp, P-glycoprotein; DDI, drug-drug interaction; LC/MS/MS, liquid chromatography coupled to tandem mass spectrometry; fm, fraction of metabolism by a given enzyme; fA, fraction of activity remaining of a given enzyme in the presence of inhibitor.

    • Received September 24, 2007.
    • Accepted March 31, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (7)
Drug Metabolism and Disposition
Vol. 36, Issue 7
1 Jul 2008
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Research ArticleArticle

Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. III. In Vitro-in Vivo Correlation with Fluconazole

Chuang Lu, Cicely Berg, Shimoga R. Prakash, Frank W. Lee and Suresh K. Balani
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1261-1266; DOI: https://doi.org/10.1124/dmd.107.019000

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Research ArticleArticle

Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. III. In Vitro-in Vivo Correlation with Fluconazole

Chuang Lu, Cicely Berg, Shimoga R. Prakash, Frank W. Lee and Suresh K. Balani
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1261-1266; DOI: https://doi.org/10.1124/dmd.107.019000
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