TOXCard: Metabolism Toxicokinetics

Authors: Alexander M. Mozeika, PharmD (MS3, Rutgers New Jersey Medical School), Cynthia Santos, MD (Assistant Professor Emergency Medicine, Medical Toxicology, Rutgers New Jersey Medical School) // Reviewed by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case:¹

A 29-year-old female patient on clozapine develops oropharyngeal candidiasis and is prescribed fluconazole. She subsequently develops nausea, vomiting, and ST elevations in all 12 ECG leads. Her clozapine level resulted at 542 ng/mL.

Questions:

• What are the pharmacokinetic factors of metabolism?
• How are these factors altered in the setting of toxicology (i.e. toxicokinetics)?

Background:^2,3

• Metabolism is a complex biochemical process that usually involves multiple steps.
  • Xenobiotics can be metabolized for elimination, intermediate metabolites, or active chemical moieties.
  • Metabolic processes are closely linked to elimination.
• Generally, two phases exist to increase the hydrophilicity of the compound:
  • Phase 1 – oxidation-reduction reactions (expose polar groups)
    • Ex: hydrolysis, oxidation, reduction, or dealkylation
  • Phase 2 – conjugation reactions (attaching polar moieties)
    • Ex: glucuronidation, sulfation, acetylation, carboxylation, amination, glycination, and glutathionylation
  • Cytochrome p450 (CYP450) is a family of enzymes that perform most of the phase 1 reactions.
    • The nomenclature is shown below:⁴

Image: Mittal B, Tulsyan S, Kumar S, Mittal RD, Agarwal G. Cytochrome P450 in cancer susceptibility and treatment. Advances in clinical chemistry. Vol 71: Elsevier; 2015:77-139.

• Families and subfamilies of these enzymes can share consider substrate specificity.
• Numerous xenobiotics can be metabolized by a single CYP450 enzyme.
  • Further, numerous CYP450 enzymes can metabolize the same xenobiotic.
• Other miscellaneous metabolic pathways exist and are of minimal clinical significance.⁵

Toxicokinetics of Metabolism:

• Toxic Metabolites:
  • Various metabolic processes can make a parent compound more toxic to tissues
    • Ex: acetaminophen is metabolized to NAPQI, a hepatotoxin, by CYP2E1.
  • Inhibiting this metabolism is important for mitigating toxicity.
    • However, it is often not a feasible therapeutic option.
  • Pearl: Upregulation of CYP450 enzymes can increase toxicity of xenobiotics used at appropriate doses.
    • Ex: chronic alcohol abuse greatly upregulates CYP2E1 increasing the toxic potential of acetaminophen in those patients.
  • Drug-drug interactions:
    • Xenobiotics that undergo the same metabolic pathways can compete with each other.
      • Pearl: this can cause compounds to display non-linear kinetic elimination profiles.

Main Point:

• Metabolism is the process of biochemical transformation of xenobiotics in preparation of elimination.
• A majority of the body’s metabolic pathways involve CYP450 enzymes.
• In toxicology, the metabolic processes can either be upregulated, downregulated, or inhibited, leading to a derangement of the normal physiologic response to a xenobiotic.
• Metabolism of a parent compound may also transform the xenobiotic into a more toxic entity.

References:

1. Cadeddu G, Deidda A, Stochino ME, Velluti N, Burrai C, Zompo M. Clozapine toxicity due to a multiple drug interaction: a case report. Journal of medical case reports. 2015;9(1):77.
2. Abraham T, Adams M. Pharmacogenetics and Drug Metabolism. In: Shargel L, Yu ABC, eds. Applied Biopharmaceutics & Pharmacokinetics, 7e. New York, NY: McGraw-Hill Education; 2016.
3. Hilal-Dandan R, Brunton LL. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination. Goodman and Gilman’s Manual of Pharmacology and Therapeutics, 2e. New York, NY: McGraw-Hill Education; 2016.
4. Mittal B, Tulsyan S, Kumar S, Mittal RD, Agarwal G. Cytochrome P450 in cancer susceptibility and treatment. Advances in clinical chemistry. Vol 71: Elsevier; 2015:77-139.
5. Fisher DM, Canfell PC, Fahey MR, et al. Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination. Anesthesiology. 1986;65(1):6-12.