title: New natural amino acid-bearing prodrugs boost pterostilbene's oral pharmacokinetic and distribution profile.
abstract: The biomedical effects of the natural phenol pterostilbene are of great interest but its bioavailability is negatively affected by the phenolic group in position 4' which is an ideal target for the conjugative enzymes of phase II metabolism. We report the synthesis and characterization of prodrugs in which the hydroxyl moiety is reversibly protected as a carbamate ester linked to the N-terminus of a natural amino acid. Prodrugs comprising amino acids with hydrophobic side chains were readily absorbed after intragastric administration to rats. The Area Under the Curve for pterostilbene in blood was optimal when prodrugs with isoleucine or β-alanine were used. The prodrug incorporating isoleucine was used for further studies to map distribution into major organs. When compared to pterostilbene itself, administration of the isoleucine prodrug afforded increased absorption, reduced metabolism and higher concentrations of pterostilbene, sustained for several hours, in most of the organs examined. Experiments using Caco-2 cells as an in vitro model for human intestinal absorption suggest that the prodrug could have promising absorption profiles also in humans; its uptake is partly due to passive diffusion, and partly mediated by H+-dependent transporters expressed on the apical membrane of enterocytes, such as PepT1 and OATP.
authors.affiliation: University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy; CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Azzolini
authors.affiliation: University of Padova, Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattarei
authors.affiliation: University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: La Spina
authors.affiliation: University of Padova, Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Fanin
authors.affiliation: University of Padova, Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Chiodarelli
authors.affiliation: University of Padova, Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Romio
authors.affiliation: University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy; CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Zoratti
authors.affiliation: University of Padova, Department of Chemical Sciences, Via F. Marzolo 1, 35131 Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Paradisi
authors.affiliation: University of Padova, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy; CNR Neuroscience Institute, Viale G. Colombo 3, 35121 Padova, Italy. Electronic address: lucia.biasutto@cnr.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Biasutto
mesh_terms: D000284:Administration, Oral; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002219:Carbamates / Q000737:chemistry; D045744:Cell Line, Tumor; D004952:Esters / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013267:Stilbenes / Q000737:chemistry* / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000596:Amino Acids; D002219:Carbamates; D004952:Esters; D011355:Prodrugs; D013267:Stilbenes; C107773:pterostilbene
keywords: Amino acids; Carbamate; Pharmacokinetics; Prodrugs; Pterostilbene