TOXCard: Distribution Toxicokinetics
A 23-year-old man who has been on a strict diet for several months presents with vertical nystagmus, tremors, and diplopia. He has a history of epilepsy managed with phenytoin. He reports compliance with his medications and takes them as prescribed. His phenytoin levels for the last five years have always ranged between 16-18 mg/dL.
- What are the pharmacokinetic factors affecting distribution?
- How are these factors altered in the setting of poisoning (i.e. toxicokinetics)?
- Distribution describes the transfer of a xenobiotic in body sites
- Single or multi-compartment models can mathematically describe the distribution
- Xenobiotics reach steady state after 3-5 half-lives (~5 in most cases)
- Various factors affect distribution including protein-binding, lipophilicity, etc.
- Volume of distribution (Vd) – a conceptual descriptor of where the substance is in the body relative to the plasma
- It is an “apparent” or theoretical volume and can be larger than the entire body
Toxicokinetics of Distribution:
- Enterohepatic Recirculation:4
- Involves substances (e.g. bile salts, drugs) that are metabolized by the liver, excreted into the bile, and delivered to the intestines; there they are reabsorbed across the intestinal mucosa and returned to the liver via portal circulation (see figure below)
- Numerous xenobiotics undergo enterohepatic recirculation
- Ex: valproic acid, warfarin, digoxin, amiodarone, morphine, rifampin
- These medications may exhibit prolonged toxicity
- Given their reentry into the GI tract, multi-dose activated charcoal is a potential therapy for substances that have high enterohepatic recirculation
- Activated charcoal dose : 12.5 g/hr in divided doses (e.g. 50g Q4hr)
- Volume of Distribution:1
- Pearl: Volume of distribution is a large factor determining the feasibility of a substance being dialyzed
- Substances with large Vd (>1 L/kg) have lower concentrations in the plasma and thus are unlikely to be dialyzable
- Substances with small Vd are more likely to be dialyzed because they primarily exist in the plasma space
- Ex: alcohol, lithium, salicylates, phenytoin, phenobarbital, and valproic acid
- Substances can bind to plasma proteins, namely albumin
- Thus, changes in albumin can affect overall free xenobiotic concentrations
- Also, substances that compete for the same protein-binding sites can greatly increase each other’s free concentrations
- Following exposure to a high-dose of xenobiotic, binding sites can be saturated leading to non-linear kinetics
The patient has been severely malnourished, and follow-up labs revealed an albumin of 2 g/dL. Hypoalbuminemia causes alterations in protein-binding of phenytoin. An albumin of 2 g/dL results in approximately a doubling of free phenytoin.
- Corrected phenytoin = measured phenytoin/[(0.2 x albumin) + 0.1]
- At albumin of 4.0 g/dL with measured phenytoin of 16 mg/dL, the corrected phenytoin level is 17.8 mg/dL
- At albumin of 2.0 g/dL with measured phenytoin of 16 mg/dL, the corrected phenytoin level is 32 mg/dL
- Distribution is an abstract pharmacokinetic principle that has numerous implications in toxicological emergencies – both in toxicity course and management
- Substances with small volumes of distribution and small molecular weights may easily be dialyzed
- Substances that undergo enterohepatic recirculation may be eliminated through multi-dose activated charcoal with an extended window of administration
- Protein-binding is an important pathoetiology of toxicity secondary to high-dose ingestions and drug-drug interactions
- 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.
- Shargel L, Yu ABC. Introduction to Biopharmaceutics and Pharmacokinetics. In: Shargel L, Yu ABC, eds. Applied Biopharmaceutics & Pharmacokinetics, 7e. New York, NY: McGraw-Hill Education; 2016.
- 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.
- Gao Y, Shao J, Jiang Z, et al. Drug enterohepatic circulation and disposition: constituents of systems pharmacokinetics. Drug discovery today. 2014;19(3):326-340.
- Kiang TK, Ensom MH. A comprehensive review on the predictive performance of the Sheiner-Tozer and derivative equations for the correction of phenytoin concentrations. Annals of Pharmacotherapy. 2016;50(4):311-325.