title: Pharmacokinetics of 1-methyl-L-tryptophan after single and repeated subcutaneous application in a porcine model.
abstract: Increased activity of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is associated with immunological and neurological disorders, and inhibition of its enzyme activity could be a therapeutic approach for treatment of these disorders. The aim of the present study was to establish a large animal model to study the accumulation of the potential IDO inhibitor 1-methyltryptophan (1-MT) in blood and different organs of domestic pigs (Sus scrofa domestica). Because 1-MT has not been previously evaluated in pigs, the pharmacokinetics of a single subcutaneous 1-MT application was investigated. Based on this kinetic study, a profile for repeated 1-MT applications over a period of five days was simulated and tested. The results show that a single administration of 1-MT increases its concentrations in blood, with the maximum concentration being obtained at 12 h. Repeated daily injections of 1‑MT generated increasing plasma concentrations followed by a steady-state after two days. Twelve hours after the final application, accumulation of 1-MT was observed in the brain and other organs, with a substantial variability among various tissues. The concentrations of 1-MT measured in plasma and tissues were similar to, or even higher, than those of tryptophan. Our data indicate that repeated subcutaneous injections of 1-MT provide a suitable model for accumulation of 1-MT in plasma and tissues of domestic pigs. These findings provide a basis for further research on the immunoregulatory functions of IDO in a large animal model.
authors.affiliation: Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Wirthgen
authors.forename: Ellen
authors.initials: E
authors.lastname: Kanitz
authors.forename: Margret
authors.initials: M
authors.lastname: Tuchscherer
authors.forename: Armin
authors.initials: A
authors.lastname: Tuchscherer
authors.forename: Grazyna
authors.initials: G
authors.lastname: Domanska
authors.forename: Werner
authors.initials: W
authors.lastname: Weitschies
authors.forename: Anne
authors.initials: A
authors.lastname: Seidlitz
authors.forename: Eberhard
authors.initials: E
authors.lastname: Scheuch
authors.forename: Winfried
authors.initials: W
authors.lastname: Otten
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D007279:Injections, Subcutaneous; D023421:Models, Animal; D013552:Swine / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; C525396:1-methyltryptophan