Correlation of plasma and peritoneal diasylate clomipramine concentration with hemodynamic recovery after intralipid infusion in rabbits.
OBJECTIVE
Drug sequestration to an expanded plasma lipid phase has been proposed as a potential mechanism of action for lipid emulsions in lipophilic cardiotoxin overdose. The authors set out to document plasma and peritoneal diasylate clomipramine concentration after resuscitation with lipid emulsion in a rabbit model of clomipramine-induced hypotension.


METHODS
Twenty sedated mechanically ventilated New Zealand White rabbits were allocated to receive either 12 mL/kg 20% Intralipid or 12 mL/kg saline solution, following clomipramine infusion to 50% baseline mean arterial pressure (MAP). Hemodynamic parameters and serum clomipramine concentration were determined to 59 minutes. Peritoneal dialysis with 20% Intralipid or saline solution was evaluated for clomipramine concentration.


RESULTS
Mean arterial pressure was greater in lipid-treated animals as assessed by repeated-measures analysis of variance (F[1,14] = 6.84; p = 0.020). Lipid infusion was associated with elevated plasma clomipramine concentration and reduced initial volume of distribution (Vd; 5.7 [+/-1.6] L/kg lipid vs. 15.9 [+/-7.2] L/kg saline; p = 0.0001). Peritoneal diasylate clomipramine concentration was greater in lipid-treated animals (366.2 [+/-186.2] microg/L lipid vs. 37.7 [+/-13.8] microg/L saline; p = 0.002).


CONCLUSIONS
Amelioration of clomipramine-induced hypotension with lipid infusion is associated with reduced initial Vd and elevated plasma clomipramine concentration consistent with intravascular drug-lipid sequestration. Concomitant peritoneal dialysis with lipid emulsion enhances clomipramine extraction.
Harvey
Martyn
M
Department of Emergency Medicine, Waikato Hospital, Hamilton, New Zealand. harveym@waikatodhb.govt.nz
Cave
Grant
G
Hoggett
Kerry
K
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002997:Clomipramine / Q000009:adverse effects / Q000032:analysis* / Q000097:blood; D015314:Dialysis Solutions / Q000737:chemistry*; D004195:Disease Models, Animal; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D010530:Peritoneal Dialysis; D011817:Rabbits
D015314:Dialysis Solutions; D005217:Fat Emulsions, Intravenous; D002997:Clomipramine