This study aimed to investigate the impacts of aqueous solubility, fasting, dose escalation, and dosing route on its bioavailability in Sprague-Dawley rats. Upon intravenous administration (2.5 mg/kg), PTS had rapid clearance (Cl = 68.2 �� 9.8 mL/min/kg) and moderate terminal elimination half-life (t1/2��z = 93.9 �� 22.3 min). Dose-escalation led to about twofold decline in clearance at the dose of 25 mg/kg (Cl = 36.4��7.8 mL/min/kg). When given in oral suspension (15 mg/kg), PTS had relatively low bioavailability (F = 15.9 �� 7.8%) while fasting substantially attenuated its bioavailability (F< 5.5 %). However, when dosed in a solution formulated with 2-hydroxypropyl-��-cyclodextrin (HP-��-CD) (15 mg/kg), PTS possessed good bioavailability (F = 59.2 �� 19.6%). Dose escalation resulted in about twofold SAHA HDAC
increase in bioavailability at the dose of 60 mg/kg. Sublingual delivery (2.5 mg/kg) led to rapid absorption and moderate bioavailability (F = 25.8 �� 13.1%). Statistical comparison clearly indicated Trametinib cell line
that the pharmacokinetics of PTS was more favorable than resveratrol. Aqueous solubility was identified as a barrier to its oral bioavailability while solubilizing PTS with HP-��-CD substantially increased its bioavailability; dose manipulation was a practical strategy to enhance its bioavailability and systemic exposure; and its delivery through oral mucosa was feasible. As PTS possessed superior pharmacokinetics, it is a favorable candidate for further development. ""Scope: Tomato is one of the most common crops worldwide and contains many beneficial compounds that improve abnormalities of lipid metabolism. However, the molecular mechanism underlying the effect of tomato on lipid metabolism is unclear. It has been commonly accepted that peroxisome proliferator-activated receptor �� (PPAR��) is one of the most important targets for ameliorating abnormalities of lipid metabolism. Therefore, we focused on the activation of PPAR�� and attempted to detect active compounds activating PPAR�� in tomato. Methods and results: To identify such active compounds, we screened fractions of tomato extracts using PPAR�� luciferase reporter assay. One fraction, rechromatographed-fraction eluted in 57?min (RF57), significantly increased PPAR�� reporter activity, in which a single compound is detected by LC/MS analysis. On the basis of LC/MS and NMR Selleck Olaparib
analyses, we determined the chemical structure of the active compound in RF57 as 9-oxo-10(E),12(E)-octadecadienoic acid (9-oxo-ODA). The RF57 fraction significantly increased the mRNA expression levels of PPAR�� target genes involved in fatty acid oxidation and O2 consumption in mouse primary hepatocytes. Furthermore, RF57 inhibited cellular triglyceride accumulation in the hepatocytes. Conclusion: These findings suggest that tomatoes containing 9-oxo-ODA that acts on PPAR�� are valuable for ameliorating abnormalities of lipid metabolism.