Transport of Thalidomide by the Human Intestinal Caco-2 Monolayers

Authors

Shufeng Zhou, University of AucklandFollow
Yan Li, University of Auckland
Phillip Kestell, University of Auckland
Peter Schafer, Celgene Corporation
Eli Chan, National University of Singapore
James W. Paxton, University of Auckland

Document Type

Article

Publication Date

3-2005

Keywords

thalidomide, intestinal, permeability, Caco-2

Digital Object Identifier (DOI)

https://doi.org/10.1007/BF03226408

Abstract

Studies in patients have indicated that the oral absorption of thalidomide is considerably variable at high doses ( > 200 mg/day). The aim of this study was to investigate the transport of racemic thalidomide using human colon cancer cell line (Caco-2) monolayers, which have been widely used to investigate drug permeability. A typical 21-day protocol was used to prepare Caco-2 monolayers. Thalidomide was determined by a validated high performance liquid chromatography method with ultraviolet detection. The integrity of Caco-2 monolayer was confirmed when the transepithelial electrical resistance (TEER) exceeded 300 Ω · cm², and the leakage of¹⁴C-manitol was < 1% per hour. Uptake of thalidomide by Caco-2 cells was very limited (up to 2.1%). The transport of thalidomide appeared to be linear up to 1 hr. Our study indicated that the permeability coefficients (P_app) of thalidomide at 2.5–300 μM from the apical (AP) to basolateral (BL) and from BL to AP side was 2–6 × 10⁻⁵ cm/sec, with a marked decrease in (P_app) values from AP to BL at increased thalidomide concentration. The transport of thalidomide was sodium-, temperature- and pH-dependent, as replacement of extracellular sodium chloride or reducing temperature and apical pH can result in significant decreases in theP_app values. Additional data indicated that transport of thalidomide is energy-dependent, as it was significantly (P < 0.05) inhibited by the ATP inhibitors, sodium azide and 2,4-dinitrophenol. In addition, DL-glutamic acid, cytidine, diprodomole, papaverine, quinidine, and cyclophosphamide significantly (P < 0.05) inhibited the transport of thalidomide, while the P-glycoprotein inhibitor verapamil and other nucleosides and nucleotides such as thymidine and guanine had no effect. These results indicated that thalidomide was rapidly transported by Caco-2 monolayers, and this might involve a saturable energy-dependent transporter.

Was this content written or created while at USF?

No

Citation / Publisher Attribution

European Journal of Drug Metabolism and Pharmacokinetics, v. 30, issues 1-2, p. 49-61

Scholar Commons Citation

Zhou, Shufeng; Li, Yan; Kestell, Phillip; Schafer, Peter; Chan, Eli; and Paxton, James W., "Transport of Thalidomide by the Human Intestinal Caco-2 Monolayers" (2005). Pharmacy Faculty Publications. 1.
https://digitalcommons.usf.edu/pharm_facpub/1