NQO1 and CYP450 reductase decrease the systemic exposure of rifampicin-quinone and mediate its redox cycle in rats.
Rifampicin (RIF) is used in regimens for infections caused by Mycobacteria accompanied by serious adverse reactions. Rifampicin-quinone (RIF-Q) is a major autoxidation product of RIF. It is not clear whether RIF-Q plays a role in RIF induced adverse reactions. Investigation of the systemic exposure of RIF-Q is helpful to better understand the role of RIF-Q in RIF induced adverse reactions. In this study, a simple and reproducible high performance liquid chromatography-mass spectrometry (LC-MS) method involving a procedure to prevent the RIF from oxidation for simultaneous quantification of RIF and RIF-Q in rat plasma has been developed and validated, and applied to elucidate the systemic exposure of RIF-Q in rats. The pharmacokinetics data showed that the systemic exposure of RIF-Q was very low (0.67% of RIF, AUC0-24) in rats after oral administration of RIF. However, RIF-Q may undergo the redox cycle in vivo by the evidence that the majority of RIF-Q was reduced to RIF after an oral dose of RIF-Q. Pretreatment with the NAD(P)H: quinone oxidoreductase 1 (NQO1) specific inhibitor dicoumarol and/or cytochrome P450 reductase (CPR) inhibitor diphenyleneiodonium suppressed the redox cycle and significantly increased the systemic exposure of RIF-Q. The inhibitors also attenuated the redox cycle induced reactive oxygen species formation and cytotoxicity in RIF-Q-treated HepG2 cells. These results indicate that NQO1 and CPR play an important role in redox cycle of RIF-Q and may thus contribute to RIF-induced adverse reactions.
Department of Pharmacology, Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi 563099, China. Electronic address: fuguoshi@hotmail.com.
Fuguo
F
Shi
Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Xiaobing
X
Li
Department of Clinical Pharmacy, Zunyi Medical University, Zunyi 563099, China.
Hong
H
Pan
Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance of Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Li
L
Ding
D000818:Animals; D002138:Calibration; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction; D011786:Quality Control; D011809:Quinones / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results; D012293:Rifampin / Q000031:analogs & derivatives / Q000737:chemistry*; D013997:Time Factors
D011809:Quinones; D017382:Reactive Oxygen Species; C027468:dehydrorifampicin; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C507703:NQO1 protein, rat; D012293:Rifampin
Instability; LC–MS; Rifampicin; Rifampicin-quinone; Systemic exposure