Use of endogenous cortisol 6β-hydroxylation clearance for phenotyping in vivo CYP3A activity in women after sequential administration of an oral contraceptive (OC) containing ethinylestradiol and levonorgestrel as weak CYP3A inhibitors

Shibasaki, Hiromi; Kuroiwa, Miyuki; Uchikura, Shinobu; Tsuboyama, Sayuri; Yokokawa, Akitomo; Kume, Miyoko; Furuta, Takahisa

doi:10.1016/j.steroids.2014.05.023

Cited by 8 publications

(15 citation statements)

References 35 publications

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“…An oral contraceptive was administered to 2 healthy female volunteers at 10:00 for 21 consecutive days, followed by a 7‐day washout period. Oral contraceptives containing 30 μg of ethinylestradiol and 50 μg of levonorgestrel (days 1‐6), 40 μg of ethinylestradiol and 75 μg of levonorgestrel (days 7‐11), and 30 μg of ethinylestradiol and 125 μg of levonorgestrel (days 12‐21) were administered . The subjects were nonsmokers who were not receiving any medication or herbal supplements.…”

Section: Methodsmentioning

confidence: 99%

Sensitive and simultaneous quantitation of 6β‐hydroxycortisol and cortisol in human plasma by LC‐MS/MS coupled with stable isotope dilution method

et al. 2018

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CYP3A phenotyping provides a means for personalized drug therapy. We focused our attention on the plasma 6β-hydroxycortisol (6β-OHF) to cortisol ratio as an index for CYP3A phenotyping. In the present study, we developed a sensitive and reliable method for the simultaneous determination of 6β-OHF and cortisol in human plasma using high-performance liquid chromatography/tandem mass spectrometry together with picolinylester derivatization or nonderivatization methods and 6β-[9,11,12,12- H ]hydroxycortisol and [1,2,4,19- C ]cortisol as internal standards for in vivo CYP3A phenotyping in humans. The lower limits of quantification were 38.513 pg/mL for 6β-OHF and 38.100 pg/mL for cortisol. The relative error and relative standard deviation of the lower limits of quantification were <5% for both methods. The intra-day and inter-day assay reproducibilities of the determined 6β-OHF and cortisol concentrations were consistent with the actual amounts added as relative errors and relative standard deviations for both methods, which were <5.4% and <3.9%, respectively. Both methods were applied for the quantification of plasma 6β-OHF and cortisol concentrations in healthy subjects taking oral contraceptives. The absolute concentrations and time course of 6β-OHF and cortisol were found to be consistent when measured using the 2 methods. The ratio as an index for in vivo CYP3A activity decreased after 21 days of taking oral contraceptives for both methods. To the best of our knowledge, this is the first study reporting the detailed investigation of accuracy and precision in the simultaneous measurement of 6β-OHF and cortisol in human plasma using liquid chromatography/tandem mass spectrometry coupled with stable isotope dilution method, which can be applied to CYP3A phenotyping.

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Section: Methodsmentioning

confidence: 99%

Sensitive and simultaneous quantitation of 6β‐hydroxycortisol and cortisol in human plasma by LC‐MS/MS coupled with stable isotope dilution method

et al. 2018

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“…Using the index, we found that the intraindividual and interindividual variabilities in CYP3A activity in healthy subjects were 1.1-2.5-fold and 1.5-3.4-fold, respectively, 18 and that the oral contraceptive intake reduced their CYP3A activity levels by 43% to 59%. 19 Moreover, we showed that the plasma endogenous concentration ratio of 6β-OHF to cortisol was closely related to 6βhydroxylation clearance. 20 The plasma endogenous 6β-OHF/cortisol concentration ratio is a less invasive index for evaluating CYP3A activity because this index involves single blood sampling without the administration of probe drugs for the evaluation of CYP3A activity.…”

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confidence: 85%

Dried blood spots analysis of 6β‐hydroxycortisol and cortisol using liquid chromatography/tandem mass spectrometry for calculating 6β‐hydroxycortisol to cortisol ratio

et al. 2021

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Dried blood spot (DBS) sampling is a minimally invasive method used to collect blood samples of any population for personalized medicine. We aimed to develop a sensitive and reliable analytical method for measuring 6β-hydroxycortisol (6β-OHF) and cortisol concentrations in DBS by liquid chromatography/tandem mass spectrometry so as to utilize DBS as a less invasive blood sampling method for calculating the ratio of 6β-OHF/cortisol. The lower limits of quantification obtained using four DBS were 1.08 pg/50 μl for 6β-OHF and 1.01 pg/50 μl for cortisol. The 6β-OHF and cortisol in DBS were stable for 28 days at room temperature. The intraday and interday accuracy and precision of the method was <12%. Additionally, the 6β-OHF and cortisol in DBS were measured before, during, and after 3 days of clarithromycin administration to two of the subjects. Then, their concentration was compared in the plasma and whole blood collected simultaneously. The concentrations of 6β-OHF and cortisol in four DBS ranged from 0.007 to 0.079 ng/50 μl and from 1.15 to 6.66 ng/50 μl, respectively. The 6β-OHF/cortisol ratio in DBS decreased by approximately 50% on administering clarithromycin compared with that before the administration of clarithromycin. The 6β-OHF/cortisol ratio in DBS also showed a strong correlation with that in whole blood (r = 0.9694) and plasma (r = 0.9383). This method provides high accuracy and precision for measuring 6β-OHF and cortisol in DBS. It also allows the use of DBS instead of plasma for calculating the 6β-OHF/cortisol ratio. The 6β-OHF/cortisol ratio could be an index of CYP3A activity in clinical setting.

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“…There have been encouraging results when CYP3A endogenous biomarkers have been used to capture potential DDIs during early drug development, as well as to guide the design of clinical studies [ 1 ]. Cortisol, cortisone, and dehydroepiandrosterone (DHEA) are extensively metabolised by CYP3A4, with urinary 6β-hydroxycortisol/cortisol and 6β-hydroxycortisone/cortisone ratios being shown to be useful CYP3A activity predictors [ 1 , 9 , 10 , 11 , 12 ]. The plasma concentration of 4β-hydroxycholesterol (4βHC) has also been suggested as a potential endogenous CYP3A biomarker [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug–Drug Interaction in Healthy Volunteers

Thelingwani

Diczfalusy

et al. 2021

JPM

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In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug–drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ; 100 mg once daily; n = 10), fluconazole (FKZ; 50 mg once daily; n = 9), or alprazolam (APZ; 1 mg once daily; n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1β-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1β-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (rs = 0.53, p < 0.01). The half-life of urinary endogenous 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug–drug interaction in clinical studies.

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Use of endogenous cortisol 6β-hydroxylation clearance for phenotyping in vivo CYP3A activity in women after sequential administration of an oral contraceptive (OC) containing ethinylestradiol and levonorgestrel as weak CYP3A inhibitors

Cited by 8 publications

References 35 publications

Sensitive and simultaneous quantitation of 6β‐hydroxycortisol and cortisol in human plasma by LC‐MS/MS coupled with stable isotope dilution method

Sensitive and simultaneous quantitation of 6β‐hydroxycortisol and cortisol in human plasma by LC‐MS/MS coupled with stable isotope dilution method

Dried blood spots analysis of 6β‐hydroxycortisol and cortisol using liquid chromatography/tandem mass spectrometry for calculating 6β‐hydroxycortisol to cortisol ratio

Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug–Drug Interaction in Healthy Volunteers

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