GC-MS-based quantitative signatures of cytochrome P450-mediated steroid oxidation induced by rifampicin
- GC-MS-based quantitative signatures of cytochrome P450-mediated steroid oxidation induced by rifampicin
- 문주연; 강세미; 이정애; 조주연; 문명희; 장인진; 정봉철; 최만호
- cytochrome P450; steroid; hydroxylation; refampicin; GC-MS; signatures
- Issue Date
- Therapeutic drug monitoring
- VOL 35, NO 4, 473-484
- Background: Drug-induced cytochrome P450 (CYP) activity affects endocrine function and drug clearance rates, leading to the development of unpredictable pathologic and toxicologic risks. Methods: Urinary steroid profiling based on gas chromatography-mass spectrometry (GC-MS) was used for simultaneous quantification of CYP-mediated regioselective hydroxysteroids and their substrates, including 26 androgens, 9 estrogens, 5 progestins, and 7 corticoids. The quantitative data were visualized using a hierarchically clustered heat map to allow identification of CYP-mediated steroid signatures. Twelve healthy subjects were orally administered 600 mg of rifampicin a day for 7 days, and their CYP enzyme activity was evaluated. Results: Using GC-MS, all 47 steroids were well separated with good peak shapes. This assay had good linearity (r2 > 0.994) in a dynamic range, and the interassay imprecision (% CV) and inaccuracy (% bias) were 3.0%-15.6% and 98.0%-109.2%, respectively. Administration of the CYP3A4 inducer rifampicin produced distinct differences in CYP3A4 and CYP11B1, CYP19A1, HSD11B, and HSD17B, which were indicated by their heat map-visualized steroid signatures. Conclusions: This CYP-mediated steroid signature profile allows simultaneous assessment of CYP1A, CYP1B, CYP2C, CYP3A, CYP11B, CYP17A, CYP19A, and CYP21A in urine samples. This method could therefore be a useful tool for assessing drug efficacy.
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