title: Simultaneous pharmacokinetic modeling of alkylresorcinols and their main metabolites indicates dual absorption mechanisms and enterohepatic elimination in humans.
abstract: BACKGROUND
  Alkylresorcinols have proven to be useful biomarkers of whole-grain wheat and rye intake in many nutritional studies. To improve their utility, more knowledge regarding the fate of alkylresorcinols and their metabolites after consumption is needed.
  
  
  OBJECTIVE
  The objective of this study was to develop a combined pharmacokinetic model for plasma concentrations of alkylresorcinols and their 2 major metabolites, 3,5-dihydroxybenzoic acid (DHBA) and 3-(3,5-dihydroxyphenyl)-propanoic acid (DHPPA).
  
  
  METHODS
  The model was established by using plasma samples collected from 3 women and 2 men after a single dose (120 g) of rye bran and validated against fasting plasma concentrations from 8 women and 7 men with controlled rye bran intake (23, 45, or 90 g/d). Alkylresorcinols in the lymph and plasma of a pig fed a single alkylresorcinol dose (1.3 mmol) were quantified to assess absorption. Human ileostomal effluent and pig bile after high and low alkylresorcinol doses were analyzed to evaluate biliary alkylresorcinol metabolite excretion.
  
  
  RESULTS
  The model contained 2 absorption compartments: 1 that transferred alkylresorcinols directly to the systematic circulation and 1 in which a proportion of absorbed alkylresorcinols was metabolized before reaching the systemic circulation. Plasma concentrations of alkylresorcinols and their metabolites depended on absorption and formation, respectively, and the mean ± SEM terminal elimination half-life of alkylresorcinols (1.9 ± 0.59 h), DHPPA (1.5 ± 0.26 h), and DHBA (1.3 ± 0.22 h) did not differ. The model accurately predicted alkylresorcinol and DHBA concentrations after repeated alkylresorcinol intake but DHPPA concentration was overpredicted, possibly because of poorly modeled enterohepatic circulation. During the 8 h following administration, <2% of the alkylresorcinol dose was recovered in the lymph. DHPPA was identified in both human ileostomal effluent and pig bile, indicating availability of DHPPA for absorption and enterohepatic circulation.
  
  
  CONCLUSIONS
  Intact alkylresorcinols have advantages over DHBA and DHPPA as plasma biomarkers for whole-grain wheat and rye intake because of lower susceptibility to factors other than alkylresorcinol intake.
authors.affiliation: Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, and matti.marklund@pubcare.uu.se.
authors.forename: Matti
authors.initials: M
authors.lastname: Marklund
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Strömberg
authors.affiliation: Department of Animal Science, Aarhus University, Tjele, Denmark.
authors.forename: Helle N
authors.initials: HN
authors.lastname: Lærke
authors.affiliation: Department of Animal Science, Aarhus University, Tjele, Denmark.
authors.forename: Knud E Bach
authors.initials: KE
authors.lastname: Knudsen
authors.affiliation: Department of Food Science, College of Food and Agriculture, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Afaf
authors.initials: A
authors.lastname: Kamal-Eldin
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hooker
authors.affiliation: Department of Food Science, BioCenter, Swedish University of Agricultural Sciences, Uppsala, Sweden; and Nutritional Epidemiology Unit, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Landberg
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D062385:Hydroxybenzoates / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008196:Lymph / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010667:Phenylpyruvic Acids; D012118:Resorcinols / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D012434:Secale / Q000737:chemistry; D013552:Swine
chemical_list: D062385:Hydroxybenzoates; D010667:Phenylpyruvic Acids; D012118:Resorcinols; C076950:alpha-resorcylic acid; C019344:3,4-dihydroxyphenylpyruvic acid