MADBio Lab

Modeling for Accelerated Discovery in Biology

Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity: A Physiologically Based Pharmacokinetic Model Study

Journal article

I. Kuo, B. Akpa
Anesthesiology, 2013
Semantic Scholar DOI PubMed
Cite

Cite

APA   Click to copy
Kuo, I., & Akpa, B. (2013). Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity: A Physiologically Based Pharmacokinetic Model Study. Anesthesiology.

Chicago/Turabian   Click to copy
Kuo, I., and B. Akpa. “Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity: A Physiologically Based Pharmacokinetic Model Study.” Anesthesiology (2013).

MLA   Click to copy
Kuo, I., and B. Akpa. “Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity: A Physiologically Based Pharmacokinetic Model Study.” Anesthesiology, 2013.

BibTeX   Click to copy 

@article{i2013a,
  title = {Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity: A Physiologically Based Pharmacokinetic Model Study},
  year = {2013},
  journal = {Anesthesiology},
  author = {Kuo, I. and Akpa, B.}
}

Abstract

Background

In vitro observations support the lipid sink theory of therapeutic action by confirming the capacity of lipid emulsions to successfully uptake bupivacaine from aqueous media. However, competing hypotheses and some in/ex vivo small animal studies suggest that a metabolic or positive inotropic effect underlies the dramatic effects of lipid therapy. Controlled clinical tests to establish causality and mechanism of action are an impossibility. In an effort to quantitatively probe the merits of a “sink” mechanism, a physiologically based pharmacokinetic model has been developed that considers the binding action of plasma lipid.

Methods

The model includes no fitting parameters and accounts for concentration dependence of plasma protein and lipid:anesthetic binding as well as the metabolism of the lipid scavenger. Predicted pharmacokinetics were validated by comparison with data from healthy volunteers administered a nontoxic dose of bupivacaine. The model was augmented to simulate lipid therapy and extended to the case of accidental IV infusion of bupivacaine at levels known to cause systemic toxicity.

Results

The model yielded quantitative agreement with available pharmacokinetic data. Simulated lipid infusion following an IV overdose was predicted to yield (1) an increase in total plasma concentration, (2) a decrease in unbound concentration, and (3) a decrease in tissue content of bupivacaine.

Conclusions

Results suggest that the timescale on which tissue content is reduced varies from organ to organ, with the concentration in the heart falling by 11% within 3 min. This initial study suggests that, in isolation, the lipid sink is insufficient to guarantee a reversal of systemic toxicity.

Share