title: Comparison of permeation enhancing strategies for an oral factor Xa inhibitor using the Caco-2 cell monolayer model.
abstract: FXai, a direct inhibitor of the clotting factor Xa, provides high water solubility but poor membrane permeability due to multiple sites of ionization and a molecular weight exceeding 500 Da, making it a Class III drug according to the Biopharmaceutics Classification System. To overcome the ionization problem and increase the transcellular permeability, various ester and hydroxyamidine prodrugs exhibiting a reduced number of ionization sites were studied in the Caco-2 monolayer model for intestinal permeation. Alternatively, the potential transcellular permeation enhancement of Imwitor 742 and the potential paracellular enhancement of three chitosan formulations were investigated in the same model. FXai has an apparent permeability (P(app)) of about 1 nm/s, which is generally regarded as very low. The butylester-hydroxyamidine double-prodrug was found to provide a markedly increased permeability (40.4 nm/s) as did the co-application of chitosan (43.3 nm/s). Other prodrugs slightly increased permeability (1.3-9.2 nm/s) but were inferior to the previous attempts to enhance permeability while the Imwitor admixture showed no effect (1.1 nm/s). Moreover, a bioactivating metabolism towards the hydroxyamidine mono-prodrug was detected in the Caco-2 cell permeation model. Although esterases were overexpressed and mainly located apically, an acceptable permeation was reached. In addition, the prodrugs triggered an efflux system that is not inhibited by verapamil but by quinidine, suggesting the involvement of an organic cation transporter.
authors.affiliation: Schering AG, Pharmaceutical Development, Berlin, Germany. carsten.bruesewitz@schering.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Bruesewitz
authors.forename: Adrian
authors.initials: A
authors.lastname: Funke
authors.forename: Urte
authors.initials: U
authors.lastname: Kuhland
authors.forename: Torsten
authors.initials: T
authors.lastname: Wagner
authors.forename: Ralph
authors.initials: R
authors.lastname: Lipp
mesh_terms: D000465:Algorithms; D000990:Antithrombin III / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology; D004357:Drug Synergism; D005989:Glycerides / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D011339:Probenecid / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011802:Quinidine / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D014700:Verapamil / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005989:Glycerides; D011355:Prodrugs; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III; D048271:Chitosan; D014700:Verapamil; D011802:Quinidine; D011339:Probenecid