Abstract
We conducted a comprehensive in vivo study evaluating the influence of type 2 diabetes (T2D) on major cytochrome P450 (CYP450) activities. These activities were assessed in 38 T2D and 35 non-T2D subjects after a single oral administration of a cocktail of probe drugs: 100 mg caffeine (CYP1A2), 100 mg bupropion (CYP2B6), 250 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan (CYP2D6), 2 mg midazolam (CYP3As), and 250 mg chlorzoxazone (alone; CYP2E1). Mean metabolic activity for CYP2C19, CYP2B6, and CYP3A was decreased in subjects with T2D by about 46%, 45%, and 38% (P < 0.01), respectively. CYP1A2 and CYP2C9 activities seemed slightly increased in subjects with diabetes, and no difference was observed for CYP2D6 or CYP2E1 activities. Several covariables, such as inflammatory markers (interleukin (IL)-1ß, IL-6, gamma interferon, and tumor necrosis factor alpha), genotypes, and diabetes-related and demographic-related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform-specific manner.
Trial registration:
ClinicalTrials.gov NCT02291666.
© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Bupropion / pharmacokinetics
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Caffeine / pharmacokinetics
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Case-Control Studies
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Chlorzoxazone / pharmacokinetics
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Cytochrome P-450 CYP1A2 / metabolism
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Cytochrome P-450 CYP2B6 / metabolism
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Cytochrome P-450 CYP2C19 / metabolism
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Cytochrome P-450 CYP2C9 / metabolism
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Cytochrome P-450 CYP2D6 / metabolism
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Cytochrome P-450 CYP2E1 / metabolism
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Cytochrome P-450 CYP3A / metabolism
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Cytochrome P-450 Enzyme System / metabolism*
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Dextromethorphan / pharmacokinetics
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Diabetes Mellitus, Type 2 / enzymology*
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Diabetes Mellitus, Type 2 / metabolism
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Female
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Humans
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Interferon-gamma / metabolism
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Interleukin-1beta / metabolism
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Interleukin-6 / metabolism
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Male
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Midazolam / pharmacokinetics
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Middle Aged
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Omeprazole / pharmacokinetics
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Tolbutamide / pharmacokinetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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IL1B protein, human
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IL6 protein, human
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Interleukin-1beta
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Interleukin-6
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Tumor Necrosis Factor-alpha
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Bupropion
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Caffeine
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Dextromethorphan
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Interferon-gamma
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Cytochrome P-450 Enzyme System
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Tolbutamide
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 CYP2E1
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP2B6
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Cytochrome P-450 CYP2C19
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Cytochrome P-450 CYP2D6
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Cytochrome P-450 CYP3A
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Chlorzoxazone
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Omeprazole
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Midazolam
Associated data
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ClinicalTrials.gov/NCT02291666