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Identification of the caffeine to trimethyluric acid ratio as a dietary biomarker to characterise variability in cytochrome P450 3A activity

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Cytochrome P450 (CYP) 3A plays an important role in the metabolism of many clinically used drugs and exhibits substantial between-subject variability (BSV) in activity. Current methods to assess variability in CYP3A activity have limitations and there remains a need for a minimally invasive clinically translatable strategy to define CYP3A activity. The purpose of this study was to evaluate the potential for a caffeine metabolic ratio to describe variability in CYP3A activity.

Methods

The metabolic ratio 1,3,7-trimethyluric acid (TMU) to caffeine was evaluated as a biomarker to describe variability in CYP3A activity in a cohort (n = 28) of healthy 21 to 35-year-old males. Midazolam, caffeine, and TMU concentrations were assessed at baseline and following dosing of rifampicin (300 mg daily) for 7 days.

Results

At baseline, correlation coefficients for the relationship between apparent oral midazolam clearance (CL/F) with caffeine/TMU ratio measured at 3, 4, and 6 h post dose were 0.82, 0.79, and 0.65, respectively. The strength of correlations was retained post rifampicin dosing; 0.72, 0.87, and 0.82 for the ratios at 3, 4, and 6 h, respectively. Weaker correlations were observed between the change in midazolam CL/F and change in caffeine/TMU ratio post/pre-rifampicin dosing.

Conclusion

BSV in CYP3A activity was well described by caffeine/TMU ratios pre- and post-induction. The caffeine/TMU ratio may be a convenient tool to assess BSV in CYP3A activity, but assessment of caffeine/TMU ratio alone is unlikely to account for all sources of variability in CYP3A activity.

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Funding

This study was supported by a project grant (1100179) from the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia

    Madelé van Dyk, John O. Miners, Ashley Hopkins, Michael J. Sorich & Andrew Rowland

  2. Precision Medicine, Pfizer Worldwide Research and Development, Groton, CT, USA

    Jean-Claude Marshall & Linda S. Wood

Authors
  1. Madelé van Dyk
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  2. John O. Miners
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  3. Jean-Claude Marshall
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  4. Linda S. Wood
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  5. Ashley Hopkins
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  6. Michael J. Sorich
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  7. Andrew Rowland
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Contributions

Participated in research design: MVD, JOM, MJS, and AR.

Recruitment and screening of trial participants: MVD.

Performed sample analysis: MVD and LSW.

Performed data analysis: MVD, JCM, and AR.

Wrote or contributed to the writing of the manuscript: MVD, JOM, JCM, LSW, MJS, and AR.

Corresponding author

Correspondence to Madelé van Dyk.

Ethics declarations

The study protocol was approved by the Southern Adelaide Clinical Human Research Ethics Committee (SAHREC 11.15), and informed written consent was obtained from each participant.

Conflict of interest

All authors declare that there are no conflicts of interest. Linda S Wood and Jean-Claude Marshall are employees and stock holders of Pfizer World Wide Research and Development.

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van Dyk, M., Miners, J.O., Marshall, JC. et al. Identification of the caffeine to trimethyluric acid ratio as a dietary biomarker to characterise variability in cytochrome P450 3A activity. Eur J Clin Pharmacol 75, 1211–1218 (2019). https://doi.org/10.1007/s00228-019-02682-5

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  • DOI: https://doi.org/10.1007/s00228-019-02682-5

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