Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex...

Area of Science:

• Biochemistry
• Pharmacology
• Lipid Metabolism

Background:

• Electrophilic nitro-fatty acids (NO2-FAs) exhibit promising preclinical signaling actions and safety in early clinical trials.
• Understanding NO2-FA pharmacokinetics is challenging due to their thiol alkylation, lipid esterification, and inherent instability.

Purpose of the Study:

• To elucidate the absorption, metabolism, and distribution mechanisms of 10-nitro-oleic acid (10-NO2-OA), a key NO2-FA, in dogs following oral administration.
• To characterize the in vivo behavior and unique pharmacokinetic properties of NO2-FAs.

Main Methods:

• High-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HR-MS/MS) was employed for analysis.
• Quantitative analysis of plasma free and esterified lipid fractions, focusing on triacylglycerides (TAGs).
• Identification and characterization of novel in vivo NO2-OA isomers.

Main Results:

• A primary distribution mechanism involves the initial esterification of 10-NO2-OA into complex lipids, particularly TAGs.
• Preferential and time-dependent incorporation of 10-NO2-OA into TAGs was observed compared to its metabolite, 10-nitro-stearic acid.
• New isomers of 10-NO2-OA were identified in vivo, with their reactivity and metabolism elucidated.

Conclusions:

• NO2-FAs exhibit distinct pharmacokinetics, with complex lipid esterification being the principal route for tissue distribution.
• This esterification process protects the electrophilic nature of NO2-FAs from inactivation, enabling efficient delivery to target organs.
• The findings support the potential therapeutic applications of NO2-FAs by clarifying their in vivo behavior.