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Research ArticleArticle

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

Chuang Lu, Panos Hatsis, Cicely Berg, Frank W. Lee and Suresh K. Balani
Drug Metabolism and Disposition July 2008, 36 (7) 1255-1260; DOI: https://doi.org/10.1124/dmd.107.018796
Chuang Lu
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Panos Hatsis
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Cicely Berg
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Frank W. Lee
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Suresh K. Balani
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Abstract

Traditional cytochrome P450 (P450) based drug-drug interaction (DDI) predictions are based on the ratio of an inhibitor's physiological concentration [I] and its inhibition constant Ki. Determining [I] at the enzymatic site, although critical for predicting clinical DDIs, remains a technical challenge. In our previous study, a novel approach using cryopreserved human hepatocytes suspended in human plasma was investigated to mimic the in vivo concentration of ketoconazole at the enzymatic site (Lu et al., 2007), effectively eliminating the estimation of the elusive [I] value. P450 inhibition in this system appears to model that in vivo. Using the ketoconazole inhibition information in a human hepatocyte-plasma suspension together with quantitative P450 phenotypic information, we successfully predicted the pharmacokinetic DDIs for a small set of drugs, such as theophylline, tolbutamide, omeprazole, desipramine, midazolam, loratadine, cyclosporine, and alprazolam, as well as an investigational compound. For the applicability of this model on a wider scale the in vitro-in vivo correlation data set needed to be expanded. However, for most drugs in the literature there is not enough quantitative information on the involvement of individual P450s to predict DDIs retrospectively. To facilitate that, in this study we determined quantitative P450 phenotyping for seven marketed drugs: budesonide, buprenorphine, loratadine, sirolimus, tacrolimus, docetaxel, and methylprednisolone. Augmentation of the new data set with the one generated previously produced broader a database that provided further support for the wider applicability of this approach using ketoconazole as a potent CYP3A inhibitor. This application is predicted to be equally effective with other P450 inhibitors that are not substrates of efflux pumps.

Footnotes

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

  • doi:10.1124/dmd.107.018796.

  • ABBREVIATIONS: DDI, drug-drug interactions; P450, cytochrome P450; AUC, area under the curve; CYP3A4, CYP3A4/5; fm, relative contribution of metabolizing enzymes toward the total clearance of a compound; fA, fraction of activity of a given enzyme remaining in the presence of inhibitor.

    • Received September 7, 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. II. In Vitro-in Vivo Correlation with Ketoconazole

Chuang Lu, Panos Hatsis, Cicely Berg, Frank W. Lee and Suresh K. Balani
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1255-1260; DOI: https://doi.org/10.1124/dmd.107.018796

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Research ArticleArticle

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

Chuang Lu, Panos Hatsis, Cicely Berg, Frank W. Lee and Suresh K. Balani
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1255-1260; DOI: https://doi.org/10.1124/dmd.107.018796
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