Short Chain (≤C4) Esterification Increases Bioavailability of Rosmarinic Acid and Its Potency to Inhibit Vascular Smooth Muscle Cell Proliferation

• Published in: Frontiers in pharmacology Vol. 11; p. 609756
• Main Authors: Blažević, Tina, Reznicek, Gottfried, Ding, Limin, Yang, Gangqiang, Haiss, Patricia, Heiss, Elke H, Dirsch, Verena M, Liu, Rongxia
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 21.01.2021
• Subjects: pharmacokinetics; Pharmacology; proliferation; rosmarinic acid; rosmarinic acid esters; vascular smooth muscle cells; pharmacokinetics; rosmarinic acid; proliferation; rosmarinic acid esters; vascular smooth muscle cells
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.609756

Rosmarinic acid is a natural phenolic acid and active compound found in many culinary plants, such as rosemary, mint, basil and perilla. Aiming to improve the pharmacokinetic profile of rosmarinic acid and its activity on vascular smooth muscle cell proliferation, we generated a series of rosmarinic acid esters with increasing alkyl chain length ranging from C1 to C12. UHPLC-MS/MS analysis of rat blood samples revealed the highest increase in bioavailability of rosmarinic acid, up to 10.52%, after oral administration of its butyl ester, compared to only 1.57% after rosmarinic acid had been administered in its original form. When added to vascular smooth muscle cells , all rosmarinic acid esters were taken up, remained esterified and inhibited vascular smooth muscle cell proliferation with IC values declining as the length of alkyl chains increased up to C4, with an IC of 2.84 µM for rosmarinic acid butyl ester, as evident in a resazurin assay. Vascular smooth muscle cells were arrested in the G /G phase of the cell cycle and the retinoblastoma protein phosphorylation was blocked. Esterification with longer alkyl chains did not improve absorption and resulted in cytotoxicity in settings. In this study, we proved that esterification with proper length of alkyl chains (C1-C4) is a promising way to improve bioavailability of rosmarinic acid in rats and biological activity in rat vascular smooth muscle cells.