Assay and single dose pharmacokinetics of a novel systemic acyl coenzyme A cholesterol O-acyltransferase inhibitor, RP 73163, in rat plasma using automated solid-phase extraction with high-performance liquid chromatography.
RP 73163, (S)-2-[5-(3,5-dimethylpyrazol-1-yl)pent-1-yl]sulphinyl-4,5 diphenylimidazole (I), is a highly potent in vitro and in vivo inhibitor of acyl coenzyme A cholesterol O-acyltransferase (ACAT) (E.C. 2.3.1.26), and as such it has potential therapeutic use as a cholesterol lowering agent in man. A method has been developed for the extraction and assay of I from rat plasma, using a fully automated solid-phase extraction column (ASPEC) technique, coupled to a reversed-phase HPLC system with detection by native fluorescence. The method has been validated over the concentration range 10-500 ng/ml, with demonstrated linearity, precision and accuracy, the mean limit of detection being 6.6 +/- 1.3 ng/ml. Application of the method to the assay of samples following administration of the compound to male and female rats is reported, together with determined pharmacokinetic parameters.
Jones
G D
GD
Rhône-Poulenc Rorer, Dagenham Research Centre, Essex, UK.
Hoff
T A
TA
Gunraj
P E
PE
Facchini
V
V
Chauhan
P B
PB
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid / Q000379:methods* / Q000592:standards; D004355:Drug Stability; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; C092200:RP 73163; D002785:Sterol O-Acyltransferase