Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.
DOI: 10.1111/bcp.13884; PMCID: PMC6475679
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.
British journal of clinical pharmacology
Adolescent; Adult; Cross-Over Studies; Cytochrome P-450 CYP2A6; Female; Healthy Volunteers; Humans; Male; Metronidazole; Middle Aged; Nicotine; Nicotine Chewing Gum; Pharmacogenomic Testing; Polymorphism, Genetic; Sequence Analysis, DNA; Young Adult
genetics/pharmacogenetics); antibiotics; cytochrome P450 (pharmacokinetics); cytochrome P450 enzymes; drug metabolism
Stancil SL, Pearce RE, Tyndale RF, et al. Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults. Br J Clin Pharmacol. 2019;85(5):960-969. doi:10.1111/bcp.13884