Venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats following intravenous administration of a novel supersaturated submicron lipid emulsion.
OBJECTIVE
To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution.


METHODS
Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [14C]-tirilazad was determined by quantitative whole body autoradiography.


RESULTS
Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p > 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower V(ss), (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p < 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues.


CONCLUSIONS
Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.
Wang
Y
Y
Pharmaceutical Development, Pharmacia & Upjohn, Kalamazoo, Michigan 49007, USA. youmin.wang@am.pnu.com
Mesfin
G M
GM
Rodríguez
C A
CA
Slatter
J G
JG
Schuette
M R
MR
Cory
A L
AL
Higgins
M J
MJ
D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D004655:Emulsions / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D016166:Free Radical Scavengers / Q000009:adverse effects / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008055:Lipids / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D011281:Pregnatrienes / Q000009:adverse effects / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014680:Veins / Q000187:drug effects*
D004655:Emulsions; D016166:Free Radical Scavengers; D008055:Lipids; D011281:Pregnatrienes; C053355:tirilazad