Improved intestinal transport of PD 158473, an N-methyl-D-aspartate (NMDA) antagonist, by involvement of multiple transporters
✍ Scribed by Doo-Man Oh; Hyo-Kyung Han; Rufus M. Williamson; Christopher F. Bigge; Gordon L. Amidon; Barbra H. Stewart; Narayanan Surendran
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- English
- Weight
- 137 KB
- Volume
- 91
- Category
- Article
- ISSN
- 0022-3549
No coin nor oath required. For personal study only.
✦ Synopsis
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.