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

Br J Clin Pharmacol. 2019 May;85(5):960-969. doi: 10.1111/bcp.13884. Epub 2019 Mar 12.

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.

Keywords: (genetics/pharmacogenetics); antibiotics; cytochrome P450 (pharmacokinetics); cytochrome P450 enzymes; drug metabolism.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cross-Over Studies
  • Cytochrome P-450 CYP2A6 / genetics*
  • Cytochrome P-450 CYP2A6 / metabolism
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Metronidazole / administration & dosage
  • Metronidazole / pharmacokinetics*
  • Middle Aged
  • Nicotine / administration & dosage
  • Nicotine / pharmacokinetics*
  • Nicotine Chewing Gum
  • Pharmacogenomic Testing / methods*
  • Polymorphism, Genetic
  • Sequence Analysis, DNA
  • Young Adult

Substances

  • Nicotine Chewing Gum
  • Metronidazole
  • Nicotine
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6

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