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A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

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A Correction to this article was published on 25 July 2018

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Abstract

Purpose

To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease.

Methods

Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined.

Results

The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment.

Conclusion

The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs.

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Change history

  • 25 July 2018

    One of the authors has his name incorrectly indexed in PubMed and SpringerLink as “Laird Forrest M” (last name “Laird Forrest”). His name should index as “Forrest M. Laird” with last name as “Forrest”.

Abbreviations

CAR:

Constitutive androstane receptor

CYP:

Cytochrome P450

DBS:

Dried blood spot

GPI:

Glucose-6-phosphate isomerase

HNF-4α:

Hepatic nuclear factor-4α

HLM:

Human liver microsomes

IV:

Intravenous

LC-MS:

Liquid Chromatography-Mass Spectrometry

MDZ:

Midazolam

MLM:

Mouse liver microsomes

NCA:

Non-compartmental analysis

NCE:

New chemical entity

PBPK:

Physiologically based pharmacokinetic

PK:

Pharmacokinetics

PO:

Oral

PXR:

Pregnane X receptor

qPCR:

Quantitative polymerase chain reaction

SCID:

Severe combined immune deficient

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Acknowledgements

The authors acknowledge Michael Mohutsky for help with the in vitro metabolism work, Tom Kern (Covance Inc.) for conducting in vivo pharmacokinetic experiments, George Searfoss for CYP mRNA measurements, Bridget Morse for suggestions regarding the semi-PBPK model, and Daniel Mudra for critically reading the manuscript and providing suggestions. Eli Lilly provided support for an internship by NV and funded laboratory and animal studies. NV and MLF were partially supported by a grant from NIH (R01CA173292, PI: Forrest) during analysis and development of the model. NV was partially supported by a Higuchi Fellowship and the Department of Pharmaceutical Chemistry, The University of Kansas.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, Kansas, 66047, USA

    Ninad Varkhede & M. Laird Forrest

  2. Drug Disposition, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Nita Patel

  3. Lilly Biotechnology, Eli Lilly and Company, San Diego, California, 92121, USA

    William Chang

  4. Bioanalysis and Biotransformation, Research and Development, AbbVie, North Chicago, Illinois, USA

    Kenneth Ruterbories

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  1. Ninad Varkhede
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  2. Nita Patel
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  5. M. Laird Forrest
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Correspondence to M. Laird Forrest.

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Varkhede, N., Patel, N., Chang, W. et al. A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice. Pharm Res 35, 162 (2018). https://doi.org/10.1007/s11095-018-2447-9

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