The objectives of this application are to determine the mechanisms of hepatotoxicity of the current available pharmacoenhancers and to provide a mechanism-based guidance for development of the next generation of pharmacoenhancers with less hepatotoxicity. Ritonavir (RTV) and cobicistat (COBI) are the first and second generations of pharmacoenhancers. RTV has been known as a hepatotoxin but its mechanism remains elusive. In a recent series of clinical trials, the hepatotoxicity of RTV was significantly potentiated in subjects who were pretreated with rifampicin (RIF) or efavirenz (EFV). Both RIF and EFV are potent ligands of human pregnane X receptor (PXR), a ligand-dependent transcription factor that upregulates Cytochrome P450 3A4 (CYP3A4) in drug metabolism. Because of the inter- species differences in ligand-dependent PXR activation, we generated a double transgenic mouse model expressing human PXR and CYP3A4 (TgCYP3A4/hPXR). By using the TgCYP3A4/hPXR mice, we recapitulated RTV hepatotoxicity that occurred in clinical trials. In addition, we found that COBI can cause similar liver damage as RTV. Furthermore, our metabolomic analysis revealed that RTV and COBI undergo the same bioactivation pathways to generate toxic metabolites, which are produced by CYP3A4. Based on these preliminary data, we hypothesize that human PXR modulates RTV/COBI hepatotoxicity through CYP3A4-mediated RTV/COBI bioactivation. We also hypothesize that structural modification to bypass the bioactivation pathways of RTV and COBI will mitigate their hepatotoxicity. To test our hypothesis, we propose the following three specific aims: (1) to determine the role of human PXR in RTV/COBI hepatotoxicity; (2) to determine the role of human CYP3A4 in RTV/COBI hepatotoxicity; and (3) to explore drug design for the next generation of pharmacoenhancers with less hepatotoxicity. Accomplishment of this project will have a significant impact on the field of pharmacoenhancers, especially for their safety and future development.

Public Health Relevance

(Public health relevance statement) This project will determine the mechanism of hepatotoxicity of the current available pharmacoenhancers and provide a mechanism-based guidance for development of the next generation of pharmacoenhancers with less hepatotoxicity. The results from this project will have a significant impact on the field of pharmacoenhancers, especially for their safety and future development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI131983-01A1
Application #
9411191
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Zhang, Hao
Project Start
2017-06-26
Project End
2022-05-31
Budget Start
2017-06-26
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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