title: Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans.
abstract: To develop a physiologically based kinetic (PBK) model that describes the absorption, distribution, metabolism, and excretion of hesperidin in humans, enabling the translation of in vitro concentration-response curves to in vivo dose-response curves.
  
  
  
  The PBK model for hesperidin in humans was developed based on in vitro metabolic parameters. Hesperidin was predicted to mainly occur in the systemic circulation as different monoglucuronides. The plasma concentrations of hesperidin aglycone (hesperetin) was predicted to be <0.02 mg/L at an oral dose of 50 mg/kg bw. The developed PBK model allowed conversion of in vitro concentration-response curves for different effects to in vivo dose-response curves. The BMD05(benchmark dose for 5% response) values for protein kinase A inhibition ranged between 135 and 529 mg/kg bw hesperidin, and for inhibition of endothelial cell migration and prostaglandin E2and nitric oxide production ranged between 2.19 and 44 mg/kg bw hesperidin. These values are in line with reported human data showing in vivo effects by hesperidin and show that these effects may occur at Western dietary and supplementary intake of hesperidin.
  
  
  
  The developed PBK model adequately predicts absorption, distribution, metabolism, and excretion of hesperidin in humans and allows to evaluate the human in vivo situation without the need for human intervention studies.
authors.affiliation: Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands.
authors.forename: Rungnapa
authors.initials: R
authors.lastname: Boonpawa
authors.affiliation: Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands.
authors.forename: Albertus
authors.initials: A
authors.lastname: Spenkelink
authors.affiliation: Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands.
authors.forename: Ans
authors.initials: A
authors.lastname: Punt
authors.affiliation: Division of Toxicology, Wageningen University & Research, Wageningen, The Netherlands.
authors.forename: Ivonne M C M
authors.initials: IMCM
authors.lastname: Rietjens
mesh_terms: D000284:Administration, Oral; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006569:Hesperidin / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological
chemical_list: D006569:Hesperidin; D017868:Cyclic AMP-Dependent Protein Kinases; C013015:hesperetin
keywords: ADME; Hesperetin metabolites; Hesperidin; In vitro-in vivo extrapolation; PBK modeling