Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil

3,4-Dihydroxyphenylethanol (DOPET) is the major o-diphenol detectable in ex tra virgin olive oil, either in free or esterified form. Despite its releva nt biological effects, mainly related to its antioxidant properties, little data have been reported so far on its toxicity and metabolism. The aim of the present work is to evaluate DOPET toxicity and to investigate its molec ular pharmacokinetics by using the C-14-labeled diphenol. When orally admin istered to rats, the molecule does not show appreciable toxicity up to 2 g/ kg b.wt. To identify and quantify its metabolites, (C-14]DOPET has been syn thesized and intravenously injected in rats. The pharmacokinetic analysis i ndicates a fast and extensive uptake of the molecule by the organs and tiss ues investigated, with a preferential renal uptake. Moreover, 90% of the ad ministered radioactivity is excreted in urine collected up to 5 h after inj ection, and about 5% is detectable in feces and gastrointestinal content. T he characterization of the labeled metabolites, extracted from the organs a nd urine, has been performed by high-pressure liquid chromatography analysi s. In all the investigated tissues, DOPET is enzymatically converted in fou r oxidized and/or methylated derivatives. Moreover, a significant fraction of total radioactivity is associated with the sulfo-conjugated forms, which also represent the major urinary excretion products. On the basis of the r eported results, an intracellular metabolic pathway of exogenously administ ered DOPET, implying the involvement of catechol-O-methyltransferase, alcoh ol dehydrogenase, aldehyde dehydrogenase, and phenolsulfotransferase, has b een proposed.