title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Espinardo, Murcia, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Domínguez-Perles
authors.affiliation: Department of Research and Development, Seprox BIOTECH S.L., Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Auñón
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Espinardo, Murcia, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Ferreres
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Espinardo, Murcia, Spain. angelgil@cebas.csic.es.
authors.forename: Angel
authors.initials: A
authors.lastname: Gil-Izquierdo
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005260:Female; D006719:Homovanillic Acid / Q000652:urine; D008297:Male; D000069463:Olive Oil / Q000008:administration & dosage; D010636:Phenols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D053719:Tandem Mass Spectrometry
chemical_list: D000069463:Olive Oil; D010636:Phenols; C532664:homovanillic alcohol; D015102:3,4-Dihydroxyphenylacetic Acid; C005975:3,4-dihydroxyphenylethanol; C011867:4-hydroxyphenylethanol; D010626:Phenylethyl Alcohol; D006719:Homovanillic Acid
keywords: Bioavailability; DOPAC; Hydroxytyrosol; Hydroxytyrosol acetate; Oral administration; Plasma; Urine