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Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.

ABSTRACT: AIMS:CYP2A6 is a genetically polymorphic enzyme resulting in differential substrate metabolism and health behaviours. Current phenotyping probes for CYP2A6 exhibit limitations related to procurement (deuterated cotinine), toxicity (coumarin), specificity (caffeine) and age-appropriate administration (nicotine, NIC). In vitro, CYP2A6 selectively forms 2-hydroxymetronidazole (2HM) from metronidazole (MTZ). The purpose of this study was to evaluate MTZ as a CYP2A6 phenotyping probe drug in healthy adults against the well-established method of measuring trans-3-hydroxycotinine (3HC)/cotinine (COT). METHODS:A randomized, cross-over, pharmacokinetic study was completed in 16 healthy, nonsmoking adults. Separated by a washout period of at least 2 weeks, MTZ 500 mg and NIC gum 2 mg were administered and plasma was sampled over 48 hours and 8 hours, respectively. Correlations of plasma metabolite/parent ratios (2HM/MTZ; 3HC/COT) were assessed by Pearson coefficient. CYP2A6 genotyping was conducted and incorporated as a variable of plasma ratio response. RESULTS:Correlations between the plasma ratio 2HM/MTZ and 3HC/COT were ? 0.9 at multiple time points (P < 0.001), demonstrating a wide window during which 2HM/MTZ can be queried post-MTZ dose. CYP2A6 genotype had significant impacts on both MTZ and NIC phenotyping ratios with decreased activity predicted phenotypes demonstrating 2HM/MTZ ratios ?58% and 3HC/COT ratios ?56% compared with extensive activity predicted phenotypes at all time points examined in the study (P < 0.05). No adverse events were reported in the MTZ arm while 38% (n = 6) of participants reported mild adverse events in the NIC arm. CONCLUSIONS:Metronidazole via 2HM/MTZ performed well as a novel, safe phenotyping probe for CYP2A6 in healthy adults.

SUBMITTER: Stancil SL

PROVIDER: S-EPMC6475679 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.

Stancil Stephani L SL Pearce Robin E RE Tyndale Rachel F RF Kearns Gregory L GL Vyhlidal Carrie A CA Leeder J Steven JS Abdel-Rahman Susan S

British journal of clinical pharmacology 20190312 5

<h4>Aims</h4>CYP2A6 is a genetically polymorphic enzyme resulting in differential substrate metabolism and health behaviours. Current phenotyping probes for CYP2A6 exhibit limitations related to procurement (deuterated cotinine), toxicity (coumarin), specificity (caffeine) and age-appropriate administration (nicotine, NIC). In vitro, CYP2A6 selectively forms 2-hydroxymetronidazole (2HM) from metronidazole (MTZ). The purpose of this study was to evaluate MTZ as a CYP2A6 phenotyping probe drug in ...[more]

PMID: 30706508

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Dataset Information

Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.

Publications

Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.

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