URINARY 6β-HYDROXYCORTISOL/CORTISOL RATIO DOES NOT REFLECT &lt;I&gt;IN VIVO&lt;/I&gt; CYP3A ACTIVITY IN HUMANS

Furuta, Takahisa; Suzuki, Atsushi; Shibasaki, Hiromi; Yokokawa, Akitomo; Kasuya, Yasuji

doi:10.2133/dmpk.16.supplement_98

Cited by 10 publications

(27 citation statements)

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“…If the probe drug has multiple metabolic pathways, the fractional metabolic clearance corresponding to the pathway of interest should be an appropriate measure (Watkins, 1994). In our previous study, we provided evidence for the validity of CLm(6b) as an appropriate index for phenotyping in vivo CYP3A activity by using stable isotope methodology (Furuta et al, 2001(Furuta et al, , 2003. The method can precisely assess in vivo CYP3A activity even when there are intraindividual and interindividual variations in the cortisol metabolic clearance mediated by enzymes other than CYP3A and in the renal clearance of cortisol.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely one report indicated a diurnal rhythm, with increased levels in the evening (Ohno et al, 2000). It should be noted that the urinary ratio 6b-OHF/F is valid as the index for in vivo CYP3A activity only when the renal clearance of cortisol is consistent (Furuta et al, 2001(Furuta et al, , 2003Peng et al, 2011), because the urinary ratio 6b-OHF/F is a function of two independent parameters: metabolic clearance specific for 6b-hydroxylation and renal clearance of cortisol. By using a probe drug in phenotyping, the clearance of the drug should provide the best estimate of in vivo catalytic activity of the enzyme of interest.…”

Section: Discussionmentioning

confidence: 99%

“…Yin et al (2004) reported that there was a large interindividual variability, with a 30-fold difference, and a small intraindividual variability (CV = 31.1%) in the urinary ratio 6b-OHF/F. This indicates that the urinary ratio 6b-OHF/F should be affected by wide interindividual variability in the renal clearance of cortisol (Furuta et al, 2001(Furuta et al, , 2003.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, the CLm(6b) (Eq. 1) was calculated as X(6b) during the 2-hour urine collection period divided by the corresponding 2-hour AUC(F) (Furuta et al, 1996(Furuta et al, , 2001(Furuta et al, , 2003: Figure 1 shows the distribution of CLm(6b) in 49 healthy subjects (25 men and 24 women) aged 22-58 years (range: 28.3 6 8.8 years). The values were in the range of 1.23 and 4.75 ml/min with 3.9-fold interindividual variability of CYP3A activity.…”

Section: Chemicalsmentioning

confidence: 99%

“…We previously reported evidence for the validity of endogenous cortisol 6b-hydroxylation clearance [CLm(6b)] as a new index for in vivo CYP3A phenotyping in humans (Furuta et al, 2001(Furuta et al, , 2003. It is calculated using the amount of urinary excreted 6b-hydroxycortisol (6b-OHF) divided by the area under the plasma concentration-time curve (AUC) of cortisol (F).…”

Section: Introductionmentioning

confidence: 99%

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Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

et al. 2012

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This study was designed to evaluate the in vivo activity of cytochrome P450 3A (CYP3A) in 49 healthy Japanese subjects aged 22-58 years using endogenous cortisol 6b-hydroxylation clearance [CLm(6b)], a novel biomarker for CYP3A phenotyping. CLm(6b) in the 49 healthy subjects was 2.40 6 0.79 ml/min with an approximately 4-fold interindividual variability of CYP3A activity. The mean clearance in the 24 women was 2.50 6 0.89 ml/min; the value in the women was higher than in the 25 men (2.30 6 0.69 ml/min) by approximately 9%. We also measured the change of CLm(6b) in 14 healthy subjects in the morning at 10:00-12:00 every 2 or 3 days over a period of 36-53 days and observed a 1.5-fold to 3.4-fold dayto-day intraindividual variability in the CYP3A activity. The mean value for CLm(6b) in each subject for 36-53 days was 2.54 6 0.76 ml/min (n = 14). We also evaluated the CLm(6b) every 2 hours from 8:00-20:00 in 26 healthy subjects. The within-day intraindividual clearance variability was 1.1-fold to 2.5-fold (2.45 6 0.91 ml/min, n = 26). No characteristic diurnal rhythms were observed in the in vivo activity of CYP3A.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

et al. 2012

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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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Simultaneous determination of 6β-hydroxycortisol and cortisol in human urine by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3A activity determined by the cortisol 6β-hydroxylation clearance

Furuta

Mori

Suzuki

et al. 2004

Journal of Chromatography B

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URINARY 6β-HYDROXYCORTISOL/CORTISOL RATIO DOES NOT REFLECT <I>IN VIVO</I> CYP3A ACTIVITY IN HUMANS

Cited by 10 publications

References 0 publications

Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

Intraindividual and Interindividual Variabilities in Endogenous Cortisol 6β-Hydroxylation Clearance as an Index for In Vivo CYP3A Phenotyping in Humans

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

Simultaneous determination of 6β-hydroxycortisol and cortisol in human urine by liquid chromatography with ultraviolet absorbance detection for phenotyping the CYP3A activity determined by the cortisol 6β-hydroxylation clearance

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