Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

Carlo Barnaba; Jaydeep Yadav; Swati Nagar; Ken Korzekwa; Jeffrey P Jones

doi:10.1021/acs.molpharmaceut.6b00436

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Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

Journal article

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Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

Carlo Barnaba, Jaydeep Yadav, Swati Nagar, Ken Korzekwa and Jeffrey P Jones

Molecular pharmaceutics, Vol.13(8), pp.2833-2843

08/01/2016

DOI: https://doi.org/10.1021/acs.molpharmaceut.6b00436

Handle:

https://hdl.handle.net/2376/109614

PMCID: PMC5059843

PMID: 27336918

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https://doi.org/10.1021/acs.molpharmaceut.6b00436View

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Abstract

Models, Theoretical

Podophyllotoxin - pharmacology

Humans

Microsomes, Liver - metabolism

Rats

Male

Rats, Sprague-Dawley

Animals

Cytochrome P-450 CYP3A - metabolism

Mass Spectrometry

Chromatography, Liquid

Benzhydryl Compounds - pharmacology

Kinetics

An in vitro observation of time-dependent inhibition (TDI) of metabolic enzymes often results in removing a potential drug from the drug pipeline. However, the accepted method for predicting TDIs of the important drug metabolizing cytochrome P450 enzymes often overestimates the drug interaction potential. Better models that take into account the complexities of the cytochrome P450 enzyme system will lead to better predictions. Herein we report the use of our previously described models for complex kinetics of podophyllotoxin. Spectral characterization of the kinetics indicates that an intermediate MI complex is formed, which slowly progresses to an essentially irreversible MI complex. The intermediate MI complex can release free enzyme during the time course of a typical 30 min TDI experiment. This slow rate of MI complex conversion results in an overprediction of the kinact value if this process is not included in the analysis of the activity versus time profile. In vitro kinetic experiments in rat liver microsomes predicted a lack of drug interaction between podophyllotoxin and midazolam. In vivo rat pharmacokinetic studies confirmed this lack of drug interaction.

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Title: Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations
Creators: Carlo Barnaba - Department of Chemistry, Washington State University , Pullman, Washington 99164, United States
Jaydeep Yadav - Department of Pharmaceutical Sciences, Temple University School of Pharmacy , Philadelphia, Pennsylvania 19140, United States
Swati Nagar - Department of Pharmaceutical Sciences, Temple University School of Pharmacy , Philadelphia, Pennsylvania 19140, United States
Ken Korzekwa - Department of Pharmaceutical Sciences, Temple University School of Pharmacy , Philadelphia, Pennsylvania 19140, United States
Jeffrey P Jones - Department of Chemistry, Washington State University , Pullman, Washington 99164, United States
Publication Details: Molecular pharmaceutics, Vol.13(8), pp.2833-2843
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 GM114369 / NIGMS NIH HHS R01 GM104178 / NIGMS NIH HHS
Identifiers: 99900547347701842
Language: English
Resource Type: Journal article