Single dose pharmacokinetics of intravenous 3,4-dihydroxyphenylacetic acid and 3-hydroxyphenylacetic acid in rats.

3,4-Dihydroxyphenylacetic acid (DOPAC) and 3-hydroxyphenylacetic acid (3-HPAA) are intestinal metabolites of the dietary flavonoid quercetin. DOPAC reportedly showed anxiolytic activity after i.p. administration in rats. The fate of these metabolites after consumption, and the pharmacological properties of 3-HPAA in the body are largely unknown. The aim of the current study was to characterize pharmacokinetic properties of DOPAC and 3-HPAA after intravenous bolus application in rats. UHPLC-MS/MS methods for quantification of DOPAC and 3-HPAA levels in lithium heparin Sprague Dawley rat plasma were developed and validated according to international regulatory guidelines. Non-compartmental and compartmental analyses were performed. Pharmacokinetic profiles of DOPAC and 3-HPAA followed a two-compartment body model, with a fast distribution into peripheral tissues (half-lives of 3.27-5.26 min) and rapid elimination from the body (half-lives of 18.4-33.3 min).

Gender differences in plasma and urine metabolites from Sprague-Dawley rats after oral administration of normal and high doses of hydroxytyrosol, hydroxytyrosol acetate, and DOPAC.

PURPOSE: To date, several in vitro and in vivo studies have shown phenolic compounds occurring naturally in olives and olive oil to be beneficial to human health due to their interaction with intracellular signaling pathways. However, the bioavailability of the most important of these compounds, hydroxytyrosol (HT), and its transformation into derivatives within the organism after oral intake are still not completely understood, requiring further in vivo research. This study deals with the differential bioavailability and metabolism of oral HT and its derivatives in rats. METHODS: Hydroxytyrosol (HT), hydroxytyrosol acetate (HTA), and 2,3-dihydroxyphenylacetic acid (DOPAC) were administered at doses of 1 and 5 mg/kg to Sprague-Dawley rats (n = 9 per treatment) by oral gavage. Their plasma kinetics and absorption ratio, assessed as their excretion in 24-h urine, were determined by UHPLC/MS/MS. RESULTS: Plasma and urine levels indicated that although the three compounds are efficiently absorbed in the gastrointestinal tract and show similar metabolism, the bioavailability is strongly dependent on the derivative considered, dosage, and gender. Inter-conversion among them has been described also, suggesting an interaction with internal routes. Microbiota metabolites derived from these phenolics were also taken into account; thereby, homovanillic alcohol and tyrosol were identified and quantified in urine samples after enzymatic de-conjugation, concluding the metabolic profile of HT. CONCLUSIONS: Our results suggest that different dosages of HT, HTA, and DOPAC do not provide a linear, dose-dependent plasma concentration or excretion in urine, both of which can be affected by the saturation of first-phase metabolic processes and intestinal transporters.

Intracerebral infusion of DOPAC decreases striatal dopamine.

The purpose of this study was to determine whether elevated levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolite of dopamine (DA) in the brain, could decrease the DA content in the striatum. Levels of DA were determined by high pressure liquid chromatography with electrochemical detection (HPLC-EC) in the striatum of male rats 24 h following a single intracerebral administration of DOPAC into the right striatum. DOPAC at 16.8 micrograms reduced the DA content of the infused side by 17%, p = 0.01. In contrast, infusion of 1.68 micrograms of DOPAC or the vehicle had no effect on striatal DA levels. Coapplication of the antioxidant, ascorbic acid, at 0.2 mg/ml with 16.8 micrograms of DOPAC prevented the decrease in DA content. Furthermore, infusion of 18.2 micrograms of homovanillic acid (HVA), the product of DOPAC methylation, had no effect on striatal DA. These results indicate that DOPAC may undergo autoxidation in vivo to produce neurotoxic species which may result in reduction of striatal DA. Formation of such an autoxidation product(s) of endogenous DOPAC was verified in the extracellular fluid of striatal slices in vitro.