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Drug Metabolism and Personalized Therapy

Official journal of the European Society of Pharmacogenomics and Personalised Therapy

Editor-in-Chief: Llerena, Adrián

Editorial Board: Benjeddou, Mongi / Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario / Hubacek, Jaroslav A. / Ingelman-Sundberg, Magnus / Maitland-van der Zee, Anke-Hilse / Manolopoulos, Vangelis G. / Marc, Janja / Melichar, Bohuslav / Meyer, Urs A. / Nair, Sujit / Nofziger, Charity / Peiro, Ana / Sadee, Wolfgang / Salazar, Luis A. / Simmaco, Maurizio / Turpeinen, Miia / Schaik, Ron / Shin, Jae-Gook / Visvikis-Siest, Sophie / Zanger, Ulrich M.

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Volume 31, Issue 4

Issues

Improvement of the chemical inhibition phenotyping assay by cross-reactivity correction

Nicholas M. Njuguna
  • Corresponding author
  • The National Quality Control Laboratory, P. O. Box 29726 – 00202, KNH, Nairobi, Kenya, Phone: +254 722 904 908, Fax: +254 20 2718073
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ken-ichi Umehara
  • Department of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Felix Huth
  • Department of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland
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  • De Gruyter OnlineGoogle Scholar
/ Hilmar Schiller
  • Department of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kelly Chibale / Gian Camenisch
  • Department of Drug Metabolism and Pharmacokinetics, Integrated Drug Disposition Section, Novartis Institutes for BioMedical Research, Basel, Switzerland
  • Other articles by this author:
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Published Online: 2016-10-08 | DOI: https://doi.org/10.1515/dmpt-2016-0028

Abstract

Background:

The fraction of an absorbed drug metabolized by the different hepatic cytochrome P450 (CYP) enzymes, relative to total hepatic CYP metabolism (fmCYP), can be estimated by measuring the inhibitory effects of presumably selective CYP inhibitors on the intrinsic metabolic clearance of a drug using human liver microsomes. However, the chemical inhibition data are often affected by cross-reactivities of the chemical inhibitors used in this assay.

Methods:

To overcome this drawback, the cross-reactivities exhibited by six chemical inhibitors (furafylline, montelukast, sulfaphenazole, ticlopidine, quinidine and ketoconazole) were quantified using specific CYP enzyme marker reactions. The determined cross-reactivities were used to correct the in vitro fmCYPs of nine marketed drugs. The corrected values were compared with reference data obtained by physiologically based pharmacokinetics simulation using the software SimCYP.

Results:

Uncorrected in vitro fmCYPs of the nine drugs showed poor linear correlation with their reference data (R2=0.443). Correction by factoring in inhibitor cross-reactivities significantly improved the correlation (R2=0.736).

Conclusions:

Correcting in vitro chemical inhibition results for cross-reactivities appear to offer a straightforward and easily adoptable approach to provide improved fmCYP data for a drug.

Keywords: chemical inhibition; cross-reactivity; CYP; enzyme phenotyping; fmCYP; physiologically based pharmacokinetics (PBPK) model

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About the article

Received: 2016-08-29

Accepted: 2016-09-13

Published Online: 2016-10-08

Published in Print: 2016-12-01


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: Declaration or None declared.

Employment or leadership: Declaration or None declared.

Honorarium: Declaration or None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Drug Metabolism and Personalized Therapy, Volume 31, Issue 4, Pages 221–228, ISSN (Online) 2363-8915, ISSN (Print) 2363-8907, DOI: https://doi.org/10.1515/dmpt-2016-0028.

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