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Identification of the caffeine to trimethyluric acid ratio as a dietary biomarker to characterise variability in cytochrome P450 3A activity.
van Dyk, Madelé; Miners, John O; Marshall, Jean-Claude; Wood, Linda S; Hopkins, Ashley; Sorich, Michael J; Rowland, Andrew.
Afiliação
  • van Dyk M; Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia. madele.vandyk@flinders.edu.au.
  • Miners JO; Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia.
  • Marshall JC; Precision Medicine, Pfizer Worldwide Research and Development, Groton, CT, USA.
  • Wood LS; Precision Medicine, Pfizer Worldwide Research and Development, Groton, CT, USA.
  • Hopkins A; Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia.
  • Sorich MJ; Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia.
  • Rowland A; Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, SA, 5042, Australia.
Eur J Clin Pharmacol ; 75(9): 1211-1218, 2019 Sep.
Article em En | MEDLINE | ID: mdl-31123759
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ácido Úrico / Cafeína / Citocromo P-450 CYP3A Tipo de estudo: Diagnostic_studies Limite: Adult / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ácido Úrico / Cafeína / Citocromo P-450 CYP3A Tipo de estudo: Diagnostic_studies Limite: Adult / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article