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Drug Metabolism & Disposition

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PREDICTION OF DRUG-DRUG INTERACTIONS FROM IN VITRO INDUCTION DATA

Application of the Relative Induction Score Approach Using Cryopreserved Human Hepatocytes

Odette A. Fahmi, Sherri Boldt, Mary Kish, R. Scott Obach and Larry M. Tremaine
Drug Metabolism and Disposition September 2008, 36 (9) 1971-1974; DOI: https://doi.org/10.1124/dmd.108.021907
Odette A. Fahmi
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Sherri Boldt
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Mary Kish
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R. Scott Obach
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Larry M. Tremaine
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Application of the Relative Induction Score Approach Using Cryopreserved Human Hepatocytes

Abstract

Cytochrome P450 induction-mediated drug-drug interaction (DDI) is one of the major concerns in clinical practice and for the pharmaceutical industry. Previously, a novel approach [the relative induction score (RIS)] was developed using the Fa2N-4 immortalized human hepatocyte line and proposed as a tool for predicting magnitude of clinical DDIs caused by induction of CYP3A. The approach is based on combining in vitro induction parameters (EC50 and Emax) with the efficacious free plasma concentrations to calculate a relative induction score, which is correlated to the magnitude of clinical DDI for midazolam or ethinyl estradiol. To expand the applicability of the RIS model, we have measured induction caused by ten drugs in two different lots of human cryopreserved hepatocytes and correlated the data to clinical DDIs using the RIS. The results demonstrated that, as with Fa2N-4 hepatocytes, sigmoidal relationships can be derived between RIS and magnitude of induction of midazolam and ethinyl estradiol clearance in cryopreserved human hepatocytes. This study demonstrates the general applicability of the relative induction score approach using the human cryopreserved hepatocyte model to predict clinical DDI.

Footnotes

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

  • doi:10.1124/dmd.108.021907.

  • ABBREVIATIONS: PXR, pregnane X receptor; CAR, constitutive androstane receptor; RIS, relative induction score; DDI, drug-drug interactions; DMSO, dimethyl sulfoxide; AUC, area under the curve; RT-PCR, reverse transcription-polymerase chain reaction.

    • Received April 16, 2008.
    • Accepted May 30, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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PREDICTION OF DRUG-DRUG INTERACTIONS FROM IN VITRO INDUCTION DATA

Odette A. Fahmi, Sherri Boldt, Mary Kish, R. Scott Obach and Larry M. Tremaine
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1971-1974; DOI: https://doi.org/10.1124/dmd.108.021907

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PREDICTION OF DRUG-DRUG INTERACTIONS FROM IN VITRO INDUCTION DATA

Odette A. Fahmi, Sherri Boldt, Mary Kish, R. Scott Obach and Larry M. Tremaine
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1971-1974; DOI: https://doi.org/10.1124/dmd.108.021907
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