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dc.contributor.authorVarkhede, Ninad
dc.contributor.authorPatel, Nita
dc.contributor.authorChang, William
dc.contributor.authorRuterbories, Kenneth
dc.contributor.authorForrest, M. Laird
dc.identifier.citationVarkhede, 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/s11095-018-2447-9en_US
dc.descriptionThis is the author's accepted manuscript.en_US
dc.description.abstractPurpose 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.
dc.publisherAmerican Association of Pharmaceutical Scientistsen_US
dc.rights© Springer Science+Business Media, LLC, part of Springer Nature 2018en_US
dc.subjectDrug metabolism
dc.subjectGlucose-6-phosphate isomerase
dc.subjectInflammation physiologically based pharmacokinetic model
dc.titleA Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Miceen_US
kusw.kuauthorVarkhede, Ninad
kusw.kuauthorForrest, M. Laird
kusw.kudepartmentPharmaceutical Chemistryen_US
kusw.oanotesPer SHERPA/RoMEO, 10/31/2019 Author's Pre-print: green tick author can archive pre-print (ie pre-refereeing) Author's Post-print: green tick author can archive post-print (ie final draft post-refereeing) Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions:

Now published by Springer (1st Jan 2007) Authors own final version only can be archived Publisher's version/PDF cannot be used On author's personal website On institutional repository or funders designated website/repository after 12 months Published source must be acknowledged Must link to publisher version Set phrase to accompany link to published version: The original publication is available at Articles in some journals can be made Open Access on payment of additional charge NIH Authors can deposit in PubMed Central for public release after 12 month embargo
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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