title: Validity of the lipid sink as a mechanism for the reversal of local anesthetic systemic toxicity: a physiologically based pharmacokinetic model study.
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.
authors: Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Ilinois 60607, USA.
authors: Ilin
authors: I
authors: Kuo
authors: Belinda S
authors: BS
authors: Akpa
mesh_terms: D000779:Anesthetics, Local / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002045:Bupivacaine / Q000493:pharmacokinetics* / Q000633:toxicity*; D005217:Fat Emulsions, Intravenous / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008954:Models, Biological; D012016:Reference Values; D015203:Reproducibility of Results
chemical_list: D000779:Anesthetics, Local; D005217:Fat Emulsions, Intravenous; D002045:Bupivacaine