Assessing the plasma pharmacokinetics, tissue distribution, excretion and effects on cholesterol pharmacokinetics of a novel hydrophilic compound, FM-VP4, following administration to rats.

PURPOSE. The purpose of this project was to 1) assess the disposition kinet ics of [3H]-cholesterol following co-administration with a novel hydrophili c compound, FM-VP4, and 2) determine the pharmacokinetics, tissue distribut ion and excretion of [3H] FM-VP4 following single oral (150 mg/kg which inc ludes 100 mCi of radiolabel) and intravenous (15 mg/kg which includes 10 mC i of radiolabel) doses. METHODS. Following an overnight fast (12-16 h) and 48 h post-surgery, adult male Sprague Dawley rats were divided into six tre atment groups (n=4/group). Groups received single oral doses of 25 mCi/ml [ 3H] cholesterol alone or with 5, 10, 20, 50 and 100 mg/kg FM-VP4 at 0700 h. Ten percent Intralipid was used to solubilize and co-administer [3H]-chole sterol and FM-VP4. LC-MS analysis confirmed minimal cholesterol and vegetab le stanol content within 10% Intralipid. Thin layer chromatography was used to confirm that the majority of radioactivity measured in plasma was assoc iated with either esterified or unesterified cholesterol. In a second study pharmacokinetics of [3H] FM-VP4 were studied following intravenous or oral ly gavaged doses (n=8). Tissues, urine and feces were also collected in FM- VP4 kinetics study to measure tissue distribution of radioactivity. Plasma [3H] cholesterol and [3H] FM-VP4 were tested for radioactivity. RESULTS. FM -VP4 co-administration significantly decreased [3H]-cholesterol AUC0-48h an d Cmax, and increased CL/F and Vd/F of [3H]-cholesterol as compared to cont rols in a dose-dependent manner. Following oral administration of [3H] FM-V P4, the majority of radioactivity following was recovered in the feces and gastrointestinal (GI) tract. The compound exhibited an oral bioavailability of 6.5%. Following IV administration, a two-compartment pharmacokinetic mo del was observed and the majority of the radioactivity was recovered in the GI tract. CONCLUSIONS. FM-VP4 reduces plasma concentration of [3H]-cholest erol in fasting rats. [3H] FM-VP4 has a very low oral bioavailability.