Half-Life of Lipid Emulsions Used in Lipid Emulsion Treatment for Drug Toxicity

I read with much interest the case report titled “Successful Treatment of Amoxapine-Induced Intractable Seizures with Intravenous Lipid Emulsion,” which was recently published in The Journal of Emergency Medicine ( ). Lipid emulsion is the recommended treatment for local anesthetic systemic toxicity ( ). In addition, lipid emulsion has been reported to ameliorate the intractable cardiovascular collapse caused by toxic doses of highly lipid-soluble drugs (log P > 2), such as calcium channel blockers, antipsychotic drugs, and antidepressants ( ). Furthermore, a randomized controlled clinical study reported that lipid emulsion was effective for improving the decreased Glasgow Coma Scale score and prolonged QTc interval caused by antipsychotic clozapine toxicity ( ). In this case, an initial bolus administration of 20% Intralipid (100 mL, Intralipos injection 20%, Otsuka Pharmaceutical Factory Inc, Japan) stopped the seizures caused by tricyclic antidepressant amoxapine toxicity; however, the seizures recurred 60 min after the initial bolus administration of 20% Intralipid ( ). The recurrent seizures disappeared after four additional doses of 20% Intralipid (100 mL, four times) ( ). I would like to propose a possible mechanism associated with the seizure recurrence observed 60 min after the initial bolus administration of 20% Intralipid 100 mL ( ). The widely accepted underlying mechanism of lipid emulsion treatment as an adjuvant drug in drug toxicity is lipid shuttling ( ). In lipid shuttling, a large lipid compartment provided by intravenous administration of a lipid emulsion absorbs highly lipid-soluble drugs (e.g., log P of bupivacaine = 3.41, log P of amoxapine = 3.4) from organs with high blood flow, such as the heart, brain, and kidney; the lipid emulsion containing the offending toxicity-causing lipid-soluble drugs is then delivered to the liver, muscles, and adipose tissue for detoxification and storage ( ). The elimination half-life of amoxapine is 8 h, whereas that of the triglycerides in Intralipid is 13.7 ± 5.2 min, which is < 20 min ( , ). Thus, seizure recurrence at 60 min after the initial bolus administration of Intralipid may be associated with an interrupted scavenging effect because the half-life of Intralipid is shorter than that of amoxapine ( , , ). Similar to this case report, lipid emulsion treatment, which involves 1.5 mL/kg Intralipid followed by 0.25 mL/kg/min for 30 min, has been reported to decrease the plasma concentration of the highly lipid-soluble antidepressant trazodone; however, a rebound increase in trazodone concentration was observed after stopping the continuous infusion of lipid emulsion ( ). Furthermore, initial bolus administration of 20% Intralipid (1.5 mL/kg) improved mental status in an adolescent patient with bupropion toxicity 30 min after administering lipid emulsion; however, altered mental status reappeared on day 3 of admission, which was treated with re-administration of 20% Intralipid (1.5 mL/kg) ( ). The observed re-elevation of plasma trazodone concentration and recurrence of altered mental status may be attributed to the elimination half-life (trazodone: 10–12 h; bupropion: 29 ± 9 h) of the offending drugs exceeding the half-life of Intralipid (13.7 ± 5.2 min), which may lead to discontinuous lipid shuttle ( , , , , ). A 1% lipid emulsion is sufficient to provide positive inotropic and scavenging effects ( , ). Considering the maximum clearing capacity of Intralipid (110 ± 4 µM/L/min), the following dosing regimen of 20% lipid emulsion as an adjuvant drug for treating non–local anesthetic drug toxicity via oral administration is suggested to provide 1% plasma triglyceride: initial bolus administration of 1.5 mL/kg lipid emulsion (20%) and subsequent administration of 0.25 mL/kg lipid emulsion for an additional 3 min, followed by continuous infusion of lipid emulsion (0.025 mL/kg/min) ( , ). The recommended dose of 20% Intralipid for parenteral nutrition by the U.S. Food and Drug Administration is 12.5 mL/kg/d, this continuous infusion (0.025 mL/kg/min) of 20% Intralipid can be used for up to 400 min/d ( ). However, systemic toxicity of local anesthetics mostly occurs via intravenous administration, whereas drug toxicity caused by non–local anesthetic drugs occurs via enteral administration. Thus, the toxicokinetics of toxicity caused by local anesthetic drugs and non–local anesthetic drugs are different. Therefore, further studies are needed to examine the optimal dosing regimen of lipid emulsion treatment for drug toxicity caused by non–local anesthetic drugs via oral administration.