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Is toxicity of PMMA (paramethoxymethamphetamine) associated with cytochrome P450 pharmacogenetics?

Merete Vevelstad1, Elisabeth Leere Øiestad2, Sara Bremer3

  • 1Division of Forensic Sciences, Norwegian Institute of Public Health (NIPH), P.O. Box 4404, Nydalen, N-0403 Oslo, Norway.

Forensic Science International
|March 2, 2016
PubMed

Insights

Designer drug paramethoxymethamphetamine (PMMA) toxicity is linked to its metabolism by CYP2D6 enzymes. Fatal PMMA cases showed higher drug levels and lower metabolic ratios, suggesting rapid toxicity before extensive metabolism.

Area of Science:

  • Forensic toxicology
  • Pharmacogenetics
  • Drug metabolism

Background:

  • Designer drug paramethoxymethamphetamine (PMMA) has been associated with fatal intoxications in Norway.
  • Limited knowledge exists regarding PMMA metabolism and its role in toxicity.
  • Cytochrome P450 (CYP) 2D6 is implicated in PMMA metabolism to a psychoactive metabolite, 4-hydroxymethamphetamine (OH-MA).

Purpose of the Study:

  • To investigate the association between CYP genetics, PMMA metabolism, and the risk of fatal PMMA toxicity.
  • To compare CYP genotype and phenotype frequencies in fatal PMMA intoxications versus nonfatal abuse cases and non-abusers.

Main Methods:

  • Genotyping for clinically relevant variants of CYP2D6, CYP2C9, CYP2C19, and CYP3A5.
  • Phenotyping via blood CYP2D6 metabolic ratio (OH-MA/PMMA).
  • Comparison of genotype/phenotype distributions in fatal PMMA cases (n=17), nonfatal abuse controls (n=30), and population references (n=305).

Main Results:

  • CYP2D6 plays a role in PMMA metabolism to OH-MA, but other enzymes are also involved.
  • Fatal PMMA intoxications exhibited higher blood PMMA concentrations and lower CYP2D6 metabolic ratios compared to nonfatal abuse cases.
  • No specific CYP2D6, CYP2C9, CYP2C19, or CYP3A5 genetic marker was identified for predicting fatal PMMA toxicity.
  • An overrepresentation of CYP2D6 poor metabolizer genotype was observed in nonfatal abuse controls.

Conclusions:

  • Fatal PMMA toxicity often occurs rapidly after ingesting high doses, preceding extensive drug metabolism.
  • While CYP2D6 is involved, other enzymes contribute to PMMA biotransformation.
  • Further research is needed to explore the significance of CYP2D6 poor metabolizer status in nonfatal PMMA abuse.
Keywords:
4-MethoxymethamphetamineCYP2D6 pharmacogeneticsDesigner drugsForensic toxicologyPMMAParamethoxymethamphetamine

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