TOXCards: General Principles of Toxicokinetics

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

Case:

A 53-year-old male patient presents to the emergency department after ingestion of an unknown drug. The medical student caring for the patient wonders what clinical effects might occur and the duration of these effects.

Questions:

1. What are the general principles underlying the field of pharmacokinetics?
2. What is toxicokinetics?
3. How are these principals of clinical relevance?

Background:^1,2

• Pharmacotherapeutics is comprised of pharmacodynamics and pharmacokinetics
• Pharmacodynamics – quantitative analysis of the time-course of a xenobiotic’s effects
  • Simply, what the drug does to the body
• Pharmacokinetics – quantitative analysis of the time-course of a xenobiotic in the body
  • Simply, what the body does to the drug

Pharmacokinetics is further subdivided into ADME:³

• Most substances exhibit a dose-response relationship (i.e. increasing dose has increasing effect)⁴
• Three principles arise from this concept:
  • Threshold effect level – the lowest concentration for which there is effect
  • Dose-related response – response is proportional to dose
  • Plateau effect (ceiling effect) – maximal effect at which the dose-related response is lost

“All things are poison and nothing is without poison; only the dose makes a thing not a poison.” – Paracelsus (1493 – 1541)

Toxicokinetics:^1,2,5

• Toxicokinetics is the study of pharmacokinetics in situations of toxicology
  • These principles emerge in two situations:
    • Xenobiotics are used at higher than therapeutic dosages cause adverse effects
    • Certain xenobiotics are inherently toxic to the body
• Substantial differences exist between pharmacokinetics and toxicokinetics
  • These differences can be seen in all of the ADME principles
• Acknowledging these discrepancies is crucial for effective and appropriate clinical management

Toxicity Factors:⁴

• Numerous factors contribute to the toxicity of a xenobiotic
• Two main factors are substance tissue concentration (drug level) and the individual

Image adapted from: Santos C. Module 2: Toxicological Principles. Centers of Disease Control and Prevention Toxicological Outbreak Investigation Course.

Elimination Kinetics:^2,6

• Zero-order elimination kinetics:
  • Fixed amount of xenobiotic is eliminated per unit time
    • This represents a saturated kinetic process (i.e. enzymes and transporters are overwhelmed by substrate)
  • Large increases in plasma concentration can be seen with only small increases in dose
  • This makes it very difficult to clinical predict the rise and fall of plasma concentrations
  • Examples: ethanol, phenytoin, salicylates, omeprazole, fluoxetine, cisplatin

• First-order elimination kinetics:
  • Fixed proportion of xenobiotic is eliminated per unit time
  • Half-life is constant, regardless of substance tissue concentration
  • A large majority (~95%) substances exhibit first-order kinetics

• Michaelis-Menten kinetics:
  • A non-linear kinetic state with both zero- and first-order kinetics
  • Commonly, seen in toxicology in most situations as xenobiotic concentrations rise and transition from first order to zero order kinetics
  • Kinetics are dependent on concentration:
    • Low concentrations ([C] <<< k_m) = first-order kinetics
    • High concentrations ([C] >>> k_m) = zero-order kinetics

Main Points:

• Pharmacokinetics is the study of how the body handles a xenobiotic
  • The four main principles are ADME – absorption, distribution, metabolism, and elimination
• The toxicokinetic principles may differ greatly from traditional pharmacokinetics
  • Further, they may have significant implications in both the clinical presentation and/or treatment paradigms of toxic ingestions

References:

1. Shargel L, Yu ABC. Introduction to Biopharmaceutics and Pharmacokinetics. In: Shargel L, Yu ABC, eds. Applied Biopharmaceutics &amp; Pharmacokinetics, 7e. New York, NY: McGraw-Hill Education; 2016.
2. Howland MA. Pharmacokinetic and Toxicokinetic Principles. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies, 10e. New York, NY: McGraw-Hill Education; 2015.
3. Buxton ILO. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman &amp; Gilman’s: The Pharmacological Basis of Therapeutics, 13e. New York, NY: McGraw-Hill Education; 2017.
4. Santos C. Module 2: Toxicological Principles. . Paper presented at: Centers of Disease Control and Prevention Toxicological Outbreak Investigation Course.
5. Welling PG. Differences between pharmacokinetics and toxicokinetics. Toxicologic pathology. 1995;23(2):143-147.
6. Ducharme MP. Drug Elimination, Clearance, and Renal Clearance. In: Shargel L, Yu ABC, eds. Applied Biopharmaceutics &amp; Pharmacokinetics, 7e. New York, NY: McGraw-Hill Education; 2016.