title: Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats.
abstract: Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Bassi
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Castelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Carmi
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Scalvini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vivo
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry; D004983:Ethanolamines / Q000097:blood* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D010169:Palmitic Acids / Q000097:blood* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism*; D017208:Rats, Wistar; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D000596:Amino Acids; D004791:Enzyme Inhibitors; D004952:Esters; D004983:Ethanolamines; D010169:Palmitic Acids; D011355:Prodrugs; D000099252:Fatty Acid Amide Hydrolases; C005958:palmidrol