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NQO1 and CYP450 reductase decrease the systemic exposure of rifampicin-quinone and mediate its redox cycle in rats
Fuguo Shi1, Xiaobing Li2, Hong Pan3
1Department of Pharmacology, Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi 563099, China.
Journal of Pharmaceutical and Biomedical Analysis
|October 4, 2016
Summary
Rifampicin-quinone (RIF-Q), a product of rifampicin (RIF), has low systemic exposure in rats. However, RIF-Q undergoes a redox cycle involving NQO1 and CPR, potentially contributing to RIF-induced adverse reactions.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Rifampicin (RIF) is crucial for treating mycobacterial infections but causes serious adverse reactions.
- Rifampicin-quinone (RIF-Q) is a major RIF autoxidation product, and its role in RIF-induced adverse reactions is unclear.
- Understanding RIF-Q's systemic exposure is key to elucidating its contribution to adverse effects.
Purpose of the Study:
- To develop and validate a method for simultaneously quantifying RIF and RIF-Q in rat plasma.
- To investigate the systemic exposure and pharmacokinetic profile of RIF-Q in rats.
- To explore the role of enzymes like NAD(P)H: quinone oxidoreductase 1 (NQO1) and cytochrome P450 reductase (CPR) in RIF-Q's redox cycling and associated toxicity.
Main Methods:
- Development and validation of a high-performance liquid chromatography-mass spectrometry (LC-MS) method for RIF and RIF-Q quantification in rat plasma.
- Pharmacokinetic studies in rats following oral administration of RIF and RIF-Q.
- Inhibition studies using NQO1 (dicoumarol) and CPR (diphenyleneiodonium) inhibitors.
- Assessment of reactive oxygen species (ROS) formation and cytotoxicity in RIF-Q-treated HepG2 cells.
Main Results:
- A reproducible LC-MS method was established for simultaneous RIF and RIF-Q quantification.
- Systemic exposure of RIF-Q was low in rats after RIF administration (0.67% of RIF AUC0-24).
- RIF-Q undergoes in vivo reduction to RIF, indicating a redox cycle. Inhibition of NQO1 and CPR significantly increased RIF-Q exposure and attenuated ROS formation and cytotoxicity in HepG2 cells.
Conclusions:
- NQO1 and CPR are critical enzymes involved in the redox cycling of RIF-Q.
- The redox cycling of RIF-Q, influenced by NQO1 and CPR, may contribute to rifampicin-induced adverse reactions.
- Further investigation into the RIF-Q redox cycle is warranted to understand and mitigate RIF-associated toxicities.
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