A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice
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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.
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.
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.
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 wordscytokines drug metabolism glucose-6-phosphate isomerase inflammation physiologically based pharmacokinetic model
Constitutive androstane receptor
Dried blood spot
Hepatic nuclear factor-4α
Human liver microsomes
Liquid Chromatography-Mass Spectrometry
Mouse liver microsomes
New chemical entity
Physiologically based pharmacokinetic
Pregnane X receptor
Quantitative polymerase chain reaction
Severe combined immune deficient
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.
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