title: Improved intestinal transport of PD 158473, an N-methyl-D-aspartate (NMDA) antagonist, by involvement of multiple transporters.
abstract: The objective of this research was to determine the characteristics of intestinal transport of PD 0158473 using in vitro Caco-2 cells as well as in situ single-pass rat intestinal perfusion models. Because apical (AP)-to-basolateral (BL) transport was greater (1.8- fold) than BL-to-AP transport in the Caco-2 cell model, identification of carrier system(s) involved was further investigated. Cellular uptake of PD 0158473 was concentration and/or pH dependent and significantly inhibited by substrates of dipeptide and monocarboxylic acid transporters. Although this compound is an analog of L-Phe and previous studies demonstrated a high affinity of this compound to large neutral amino acid transporter, the involvement of amino acid carriers did not appear to be significant in the Caco-2 cell model. Subsequently, in situ single-pass intestinal perfusion studies in rats demonstrated that intestinal absorption of PD 0158473 was not concentration dependent at a concentration range tested but significantly inhibited by various dipeptides as well as substrates of dipeptide transporters. The difference in the concentration-dependent transport of PD 0158473 between Caco-2 cells and the rat perfusion model could be explained by the difference in the affinity (apparent K(m)) of PD 0158473 between Caco-2 cells (107 microM) and rat tissue (>1 mM). The present study suggested that multiple transporters are involved in the transcellular transport of this amino-acid analogue compound, of which peptide transporters could play a major role.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
authors.forename: Doo-Man
authors.initials: DM
authors.lastname: Oh
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
authors.forename: Rufus M
authors.initials: RM
authors.lastname: Williamson
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bigge
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Amidon
authors.forename: Barbra H
authors.initials: BH
authors.lastname: Stewart
authors.forename: Narayanan
authors.initials: N
authors.lastname: Surendran
mesh_terms: D000818:Animals; D019540:Area Under Curve; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009281:Naphthalenes / Q000737:chemistry / Q000493:pharmacokinetics*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D009281:Naphthalenes; C119559:PD 158473; D016194:Receptors, N-Methyl-D-Aspartate; D010649:Phenylalanine