Binding of long-lasting local anesthetics to lipid emulsions.
BACKGROUND
Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides.


METHODS
Using the shake-flask method, the authors measured the solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France).


RESULTS
The apparent distribution coefficient expressed as the ratio of mole fraction was 823 +/- 198 and 320 +/- 65 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 +/- 92 and 1,240 +/- 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration from 121 +/- 3.8 to 46 +/- 2.8 for bupivacaine, and to a lesser extent from 51 +/- 4.0 to 31 +/- 1.6 for ropivacaine. The capacity of the 1% emulsions was 871 and 2,200 microM for the 1% Medialipide and Intralipid emulsions, respectively. The dissociation constant was 818 and 2,120 microM for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. Increasing the temperature from 20 to 37 degrees C led to a greater increase in affinity for ropivacaine (55%) than for bupivacaine (27%). When the pH of the buffer was decreased from 7.40 to 7.00, the affinity was decreased by a factor of 1.68, similar for both anesthetics.


CONCLUSIONS
The solubility of long-acting local anesthetics in lipid emulsions and the high capacity of binding of these emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion Intralipid appears to be about 2.5 times more efficacious than the 50/50 medium-chain/long-chain Medialipide emulsion. Also, because of their higher hydrophobicity, racemic bupivacaine and levobupivacaine seem to clear more rapidly than ropivacaine.
Mazoit
Jean-Xavier
JX
Université Paris-Sud, Laboratoire d'Anesthésie, Faculté de Médecine, Le Kremlin Bicêtre, France. jean-xavier.mazoit@u-psud.fr
Le Guen
Régine
R
Beloeil
Hélène
H
Benhamou
Dan
D
D000465:Algorithms; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000737:chemistry*; D002021:Buffers; D002045:Bupivacaine / Q000008:administration & dosage / Q000737:chemistry; D005217:Fat Emulsions, Intravenous / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D000077212:Ropivacaine; D012995:Solubility; D013696:Temperature; D014280:Triglycerides / Q000737:chemistry
D000577:Amides; D000779:Anesthetics, Local; D002021:Buffers; D005217:Fat Emulsions, Intravenous; D014280:Triglycerides; D000077212:Ropivacaine; D002045:Bupivacaine