Dose escalation pharmacokinetic and lipid lowering activity of a novel FXR modulator: 16-Dehydropregnenalone

Abstract

The dose escalation pharmacokinetic of 16-Dehydropregnenalone and its major metabolite 5-pregnene-3β-ol-16,17-epoxy-20-one (M1) by intravenous and oral administration were studied in SD rats. Plasma concentration profile by both IV and oral route of administration shows multiple peak phenomenon indicated entrohepatic recirculation. DHP exhibits route dependent pharmacokinetic. By oral route, extensive first pass metabolism was observed which resulted in higher amount of M1 formation as compared to IV administration. Dose escalation IV administration shows non-linear increase in AUC. This was due to saturation of metabolism. In contrary systemic Cmax and AUC after oral administration shows non-linear pharmacokinetic where saturated systemic DHP and M1 pharmacokinetic was observed above 72 mg/kg, indicating saturated oral absorption. Lipid lowering activity by its oral route of administration was in accordance with its pharmacokinetic profile and reached saturation above 72 mg/kg