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

Madelé van Dyk, John O. Miners, Jean Claude Marshall, Linda S. Wood, Ashley Hopkins, Michael J. Sorich, Andrew Rowland

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1211-1218
Number of pages8
JournalEuropean Journal of Clinical Pharmacology
Volume75
Issue number9
Early online date23 May 2019
DOIs
Publication statusPublished - 1 Sept 2019

Keywords

  • Between-subject variability
  • Biomarker
  • CYP3A
  • Metabolomics
  • Phenotyping
  • Precision medicine

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