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.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Varkhede N,Patel N,Chang W,Ruterbories K,Forrest MLdoi
10.1007/s11095-018-2447-9subject
Has Abstractpub_date
2018-06-21 00:00:00pages
162issue
8eissn
0724-8741issn
1573-904Xpii
10.1007/s11095-018-2447-9journal_volume
35pub_type
杂志文章abstract：PURPOSE:Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS:We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using...
journal_title：Pharmaceutical research
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abstract：PURPOSE:To develop a new bionic system from an existing drug dissolution/absorption simulating system (DDASS) to simultaneously predict the release and absorption of enteric-coated formulations. METHODS:In accordance with the pH-dependent characteristics of enteric-coated formulations, the modified DDASS was designed ...
journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
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abstract：PURPOSE:This study aims to develop liposomal formulations containing synergistic antibiotics of colistin and ciprofloxacin for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. METHODS:Colistin (Col) and ciprofloxacin (Cip) were co-encapsulated in anionic liposomes by ammonium sulfate g...
journal_title：Pharmaceutical research
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abstract：PURPOSE:Performance of a transdermal delivery system (TDS) can be affected by exposure to elevated temperature, which can lead to unintended safety issues. This study investigated TDS and skin temperatures and their relationship in vivo, characterized the effective thermal resistance of skin, and identified the in vitr...
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更新日期：2017-07-01 00:00:00
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
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更新日期：2006-07-01 00:00:00
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更新日期：1996-07-01 00:00:00
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更新日期：1992-02-01 00:00:00
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更新日期：2013-09-01 00:00:00
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更新日期：2008-03-01 00:00:00
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更新日期：2017-10-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：1993-11-01 00:00:00
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更新日期：2011-04-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：1993-02-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：1995-03-01 00:00:00
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-004-7690-6
更新日期：2004-12-01 00:00:00
