Toxicokinetics

Key Points:

• Pharmacokinetics is the study of absorption, distribution, metabolism, and excretion of a drug
• Toxicokinetics is the study of absorption, distribution, metabolism, and excretion following a toxic exposure to a drug or other xenobiotic
• While similar in their principles, the pharmacokinetic and toxicokinetic parameters for an individual xenobiotic may differ significantly

Introduction

When consulted by health care professionals, poison center staff are often asked, “What is the half-life of this drug?” While knowing the rate of metabolism or excretion can help predict the course of an overdose, a published half-life does not always accurately reflect what happens to a drug following an overdose. Nor is half-life alone sufficient to fully explain the course of a toxic exposure. A greater knowledge of the kinetics specific to poisonings helps health care professionals better understand poisonings, as well as the challenges in predicting their course.

Pharmacokinetics is the study of a drug’s absorption, distribution, metabolism, and excretion. Common parameters include time to peak serum concentration (T_max), bioavailability (F), volume of distribution (V_d), protein-binding, and half-life (T_1/2). These values are determined by pharmacokinetic studies. Such studies are typically performed on a small number of young, healthy participants. They may use only a single dose, or repeated therapeutic doses of a drug, after which repeated blood or urine samples of the drug and its metabolites are measured. These circumstances are much different than in an overdose.

Toxicokinetics is the study of absorption, distribution, metabolism, and excretion of a drug or other xenobiotic within a toxic setting. These values are determined under far less controlled scenarios. Rather than designed trials, toxicokinetic parameters are derived from case reports and series. Often they are limited to the small number of drugs with easily-obtainable serum concentrations. Thus our knowledge of toxicokinetic values is small when compared to pharmacokinetics. However, from these limited studies we know that pharmacokinetics and toxicokinetics can differ significantly.

Differences in Pharmacokinetics and Toxicokinetics

Many examples exist of how kinetics are altered in overdose, beginning with absorption. Drugs with anticholinergic properties decrease gut motility and may increase the time to peak serum concentration.¹ Many drugs may form concretions or bezoars in the gut, leading to very prolonged absorption. Aspirin is a prime example of this- T_max following a therapeutic dose is expected in 1-2 hours, but a bezoar of aspirin tablets may continue to be absorbed over days.² Bioavailability, the percentage of drug that reaches systemic circulation, may be increased in overdose as first-pass metabolism is saturated.³

Valproic acid is an example of altered distribution in overdose. It has significant protein binding of 94% in therapeutic range, but as these proteins become saturated in overdose, the percentage of protein binding decreases as low as 15%. More free drug is available and the volume of distribution increases.⁴ Distribution into specific tissues can also be highly affected. For example, ivermectin normally has poor activity in the central nervous system due to p-glycoprotein efflux pumps. In overdose, however, these proteins are thought to become saturated leading to increased CNS penetration and neurotoxicity.⁵ 

Underlying the metabolism and excretion of a drug are enzymatic and transport processes, all of which may be saturated and slowed by an overdose. For example, hepatic metabolism of phenytoin is saturated near therapeutic levels, so half-life increases as serum levels increase. T_1/2 is 26 hours at 10 mg/L, 40 hours at 20 mg/L, and 60 hours at 40 mg/L.⁶ Another example is baclofen, which has a published half-life of 2-4 hours in therapeutic doses. It is often suggested that a serum drug level is considered negligible after five half-lives, but large baclofen overdoses have mimicked brain death far beyond five half-lives.⁷ Metabolism and excretion can also be significantly altered by the treatments given. For example, aspirin half-life in overdose is dependent on how well the urine is alkalinized⁸, and methanol half-life can range from 2.5 hours to 87 hours depending on serum concentration and whether the patient is being treated with fomepizole.⁶ Additionally, critically ill poisoned patients may have reduced perfusion or cardiac output, which decreases drug delivery to the liver and kidneys, and extends the expected half-life of a drug.³ 

Summary

Even at therapeutic doses, individual patients may have significantly varied pharmacokinetics due to age, genetic differences, and hepatic or renal impairment. These differences may become even more pronounced in toxicokinetics, where many more variables are introduced. Published pharmacokinetic data may be inaccurate or misleading when applied to a poisoned patient.

Precise predictions for any overdose is difficult due to the many variables of an overdose and the limited toxicokinetic data for most substances. However, a knowledge of toxicokinetics and consultation with a local poison control center can help better frame providers’ expectations for poisoned patients.

References

1. Rosenberg J, Benowitz NL, Pond S. Pharmacokinetics of drug overdose. Clin Pharmacokinet. 1981;6(3):161-192.
2. Wortzman DJ, Grunfeld A. Delayed absorption following enteric-coated aspirin overdose. Ann Emerg Med. 1987;16(4):434-436. doi:10.1016/s0196-0644(87)80366-9
3. Nelson LS, Howland MA, Lewin NA, et al. Pharmacokinetic and Toxicokinetic Principles. In: Goldfrank's Toxicologic Emergencies. New York, NY: McGraw-Hill Medical; 2019.
4. Ghannoum M, Laliberté M, Nolin TD, et al. Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila). 2015;53(5):454-465.
5. Edwards G. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J. 2003;2 Suppl 1:S8.
6. Olson KR, Anderson IB, Benowitz NL, et al. Poisoning & Drug Overdose. New York: McGraw Hill Education; 2018.
7. Sullivan R, Hodgman MJ, Kao L, Tormoehlen LM. Baclofen overdose mimicking brain death. Clin Toxicol (Phila). 2012 Feb;50(2):141-4.
8. Vree TB, Van Ewijk-Beneken Kolmer EW, Verwey-Van Wissen CP, Hekster YA. Effect of urinary pH on the pharmacokinetics of salicylic acid, with its glycine and glucuronide conjugates in human. Int J Clin Pharmacol Ther. 1994;32(10):550-558.

Author: Taylor Rhien, PharmD, Certified Specialist in Poison Information, Utah Poison Control Center