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Caffeine Metabolic Ratios for the In Vivo Evaluation of CYP1A2, N-acetyltransferase 2, Xanthine Oxidase and CYP2A6 Enzymatic Activities

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Phenotyping by probe substrates of cytochrome P450 (CYP) and other metabolizing enzymes is widely used to assess the effects of genes, environment and ethnicity on the in vivo metabolism of drugs and environmental chemicals. The caffeine metabolic ratio, in urine, plasma or saliva, has been used extensively as an index of CYP1A2, N-acetyltransferase 2 (NAT2), xanthine oxidase (XO) and CYP2A6 enzymatic activities. Phenotyping using plasma or saliva samples to measure the paraxanthine to caffeine (17X/137X) ratio correlates well with many measures of CYP1A2 activity. Various urinary metabolic ratios for caffeine phenotyping have been proposed, but shortcomings have been demonstrated for all the proposed urinary metabolic ratios. Several groups have proposed the urinary ratio of (1- methylxanthine (1X) + 1-methylurate (1U) + 5-acetylamino-6-formylamino-3-methyluracil (AFMU)) to 1, 7-dimethylurate (17U) i.e. (1X + 1U + AFMU)/17U as the preferred metabolic ratio for CYP1A2 activity (independent of urine flow rate). There is no consensus on the best urinary metabolic ratio for NAT2, XO or CYP2A6 enzymatic activities. Caffeine has been used by different groups to evaluate the in vivo activity of CYP1A2, NAT2, XO and CYP2A6 in different populations and the effect of many factors on these activities. Caffeine has been also used as a constituent of a “cocktail” to phenotype several enzymes simultaneously. In conclusion, phenotyping using caffeine as a probe substrate may still provide useful assessment of CYP1A2, NAT2, XO and CYP2A6 activities in epidemiologic and drug-drug interaction studies despite the limitations that are associated with its use.

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Keywords: CYP1A2; CYP2A6; Caffeine; In vivo; NAT2; Urine metabolic ratio; XO; review

Document Type: Research Article

Publication date: May 1, 2009

More about this publication?
  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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