کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1214499 | 966935 | 2010 | 5 صفحه PDF | دانلود رایگان |
Drug–drug and food–drug interactions are often due to an inhibition or induction of drug-metabolizing cytochrome P450 (CYP) enzymes and may result in non-response or adverse reactions. Hence, phenotypic biomarkers of CYP activity appear as useful tools for individualized pharmacotherapy. The metabolic ratio (MR) of the concentration of 6β-hydroxycortisol (6β-OHC) to cortisol (MR 6β-OHC/cortisol) in human urine had been proposed as an endogenous marker for CYP3A activity. Here, we report on the improvement of published LC-MS/MS methods for the simultaneous quantification of cortisol and 6β-OHC, using on-line sample cleanup by column switching and isotope-labeled analogues as internal standards. [2H2]6β-OHC was prepared by incubation of human recombinant CYP3A4 with commercially available [2H2]cortisol. Analytical sensitivity could be increased about 10-fold. The first morning urine of 69 female and 27 male healthy volunteers was analyzed for cortisol and 6β-OHC. Concentrations ranged from 1.0 to 142 and 24 to 670 ng/mL, respectively. Individual MR 6β-OHC/cortisol varied more than 20-fold and we were able to show for the first time for a Caucasian population significantly higher MR values in females as compared to males. This non-invasive biomarker for CYP3A activity lends itself for the study of genetic differences as well as enzyme induction or inhibition in the clinical setting without the need of using a probe drug.
Journal: Journal of Chromatography B - Volume 878, Issue 1, 1 January 2010, Pages 97–101