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A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice
Varkhede, Ninad Patel, Nita Chang, William Ruterbories, Kenneth Forrest, M. Laird
Varkhede, Ninad
Patel, Nita
Chang, William
Ruterbories, Kenneth
Forrest, M. Laird
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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.
Description
This is the author's accepted manuscript.
Date
2018-06-21
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Publisher
American Association of Pharmaceutical Scientists
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Research Projects
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Keywords
Cytokines, Drug metabolism, Glucose-6-phosphate isomerase, Inflammation physiologically based pharmacokinetic model
Citation
Varkhede, N., Patel, N., Chang, W., Ruterbories, K., & Forrest, M. L. (2018). A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice. Pharmaceutical research, 35(8), 162. doi:10.1007/s11095-018-2447-9