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. 2006 Aug;62(2):187-95.
doi: 10.1111/j.1365-2125.2006.02628.x.

Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity

Ya-Chi Chen  1 , S Karl Gotzkowsky, Anne N Nafziger, Robert W Kulawy, Mario L Rocci Jr, Joseph S Bertino Jr, Angela D M Kashuba
Affiliations

Poor correlation between 6beta-hydroxycortisol:cortisol molar ratios and midazolam clearance as measure of hepatic CYP3A activity

Ya-Chi Chen et al. Br J Clin Pharmacol. 2006 Aug.

Abstract

Aims: A non-invasive proposed method for measuring CYP3A activity is the urinary 6beta-hydroxycortisol:cortisol ratio. This ratio has been used as an indicator of CYP3A induction and inhibition, with mixed results. This investigation evaluated the relationship between a validated, biomarker, intravenous midazolam clearance and the urinary cortisol ratio under constitutive conditions and with the influence of a moderate CYP3A inhibitor.

Methods: This was a sequential, cross-over study design. Intravenous midazolam 0.025 mg kg(-1) was administered to 10 male and 10 female subjects once every 14 days for 4 months. Fluvoxamine 150 mg day(-1) was given to all subjects during the last two visits. Total body clearance of midazolam and urinary 6beta-hydroxycortisol:cortisol molar ratio were used as biomarkers of hepatic CYP3A activity.

Results: No significant correlations were found between these two markers (r(2) < 0.5, P > 0.05). Larger interindividual and intra-individual variability in CYP3A activity was observed in 6beta-hydroxycortisol:cortisol ratios compared with midazolam clearances. With fluvoxamine therapy, midazolam clearance values decreased approximately 1.5-fold and cortisol ratios decreased approximately 1.9-fold.

Conclusions: The high intra-individual variability of the urinary cortisol ratio, compared with midazolam, makes this a suboptimal CYP3A phenotyping tool.

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Figures

Figure 1
Figure 1
(a) Urinary 6β-hydroxycortisol:cortisol molar ratio at baseline and after treatment of fluvoxamine for men and women (the error bars indicate 5th and 95th percentile; circles indicate the outliers). (b) Midazolam plasma clearance at baseline and after treatment of fluvoxamine for men and women (the error bars indicate 5th and 95th percentile; circles indicate the outliers). Baseline (formula image) post treatment (□)
Figure 2
Figure 2
(a) Correlations between plasma midazolam clearance and urinary 6β-hydroxycortisol:cortisol molar ratio for CYP3A phenotyping in all subjects at baseline (circles, women; squares, men). (b) Correlations between plasma midazolam clearance and urinary 6β-hydroxycortisol:cortisol molar ratio for CYP3A phenotyping in all subjects post treatment (circles, women; squares, men). (c) Correlations between the changes of plasma midazolam clearance and urinary 6β-hydroxycortisol:cortisol molar ratio (post treatment/baseline) for CYP3A phenotyping in all subjects (circles, women; squares, men)
See this image and copyright information in PMC

Comment in

References

    1. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619–24. - PubMed
    1. Anzenbacher P, Anzenbacherova E. Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci. 2001;58:737–47. - PMC - PubMed
    1. Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Bacchi CE, Marsh CL, McVicar JP, Barr DM, Perkins JD, et al. Use of midazolam as a human cytochrome P4503A probe; II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation. J Pharmacol Ther. 1994;27:557–66. - PubMed
    1. Forrester LM, Henderson CJ, Glancey MJ, Back DJ, Park BK, Ball SE, Kitteringham NR, McLaren AW, Miles JS, Skett P, et al. Relative expression of cytochrome P450 isozymes in human liver and association with the metabolism of drugs and xenobiotics. Biochem J. 1992;281:359–68. - PMC - PubMed
    1. Dowling TC, Briglia AE, Fink JC, Hanes DS, Light PD, Stackiewicz L, Karyekar CS, Eddington ND, Weir MR, Henrich WL. Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther. 2003;73:427–34. - PubMed

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