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Pharmaceutical Research

, 35:162 | Cite as

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

  • Ninad Varkhede
  • Nita Patel
  • William Chang
  • Kenneth Ruterbories
  • M. Laird Forrest
Research Paper

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.

Key words

cytokines drug metabolism glucose-6-phosphate isomerase inflammation physiologically based pharmacokinetic model 

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

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

None to declare.

Supplementary material

11095_2018_2447_MOESM1_ESM.docx (2.7 mb)
ESM 1 (DOCX 2719 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ninad Varkhede
    • 1
  • Nita Patel
    • 2
  • William Chang
    • 3
  • Kenneth Ruterbories
    • 4
  • M. Laird Forrest
    • 1
  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrenceUSA
  2. 2.Drug Disposition, Lilly Corporate CenterEli Lilly and CompanyIndianapolisUSA
  3. 3.Lilly BiotechnologyEli Lilly and CompanySan DiegoUSA
  4. 4.Bioanalysis and BiotransformationResearch and Development, AbbVieNorth ChicagoUSA

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