Venoruton metabolites: pharmacological activity and kinetics

Abstract

Objective: This study was undertaken to further elucidate the mechanism of action of the phlebotonic drug Venoruton®, which is a standardized mixture of hydroxyethylrutosides (HR). Methods: First, its oral absorption in rats was compared with that of hydroxyethylquercetins (HQ), which are the hydrolysed aglycones of HR. Second, the pharmacological activity of the major HR metabolites in humans, mono-3′-hydroxyethylquercetin (mono-3′HQ) and a mixture with mono-4′HQ, were further evaluated in vitro. Results: Time to reach the maximal plasma concentration of its marker metabolite mono-4′HQ was significantly shorter after HQ than after HR administration, with an eightfold higher maximal concentration. The rapid absorption of HQ and the increased plasma levels confirm the theory that rutosides need to be hydrolysed by the intestinal microflora prior to absorption. Mono-3′HQ and, even more so, the mixture with mono-4′HQ inhibited xanthine oxidase, an enzyme responsible for the formation of reactive oxygen species, at concentrations comparable to those found in human plasma. The metabolites also inhibited the formation of superoxide radicals induced by the respiratory burst of activated HL-60 neutrophils. Both HR metabolites decreased the degree of cell death of human umbilical vein endothelial cells that were exposed to hypoxia/reoxygenation conditions, probably by scavenging destructive superoxide radicals. Conclusions: These results demonstrated new pharmacological activities, which contribute to the understanding of the mechanisms of action of HR in chronic venous insufficiency.