Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.jchromb.2004.06.009
Title: Determination of the investigational anti-cancer drug 5,6- dimethylxanthenone-4-acetic acid and its acyl glucuronide in Caco-2 monolayers by liquid chromatography with fluorescence detection: Application to transport studies
Authors: Zhou, S. 
Feng, X.
Kestell, P.
Baguley, B.C.
Paxton, J.W.
Keywords: 5,6-dimethylxanthenone-4-acetic acid
AP
apical
basolateral
BL
CYP
cytochrome P450
dimethyl sulphoxide
DMSO
DMXAA
DMXAA acyl glucuronide
DMXAA-G
Hank's balanced salt solution
HBSS
HEPES
N-[2-hydroxyethyl]piperazine-N′-[4- butanesulfonic acid]
Issue Date: 25-Sep-2004
Citation: Zhou, S., Feng, X., Kestell, P., Baguley, B.C., Paxton, J.W. (2004-09-25). Determination of the investigational anti-cancer drug 5,6- dimethylxanthenone-4-acetic acid and its acyl glucuronide in Caco-2 monolayers by liquid chromatography with fluorescence detection: Application to transport studies. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 809 (1) : 87-97. ScholarBank@NUS Repository. https://doi.org/10.1016/j.jchromb.2004.06.009
Abstract: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a potent cytokine inducer, with a bioavailability of >70% in the mouse. The aim of this study was to develop and validate HPLC methods for the determination of DMXAA and DMXAA acyl glucuronide (DMXAA-G) in the human intestinal cell line Caco-2 monolayers. The developed HPLC methods were sensitive and reliable, with acceptable accuracy (85-115% of true values) and precision (intra- and inter-assay CV < 15%). The total running time was within 6.8 min, with acceptable separation of the compounds of interest. The limit of quantitation (LOQ) values for DMXAA and DMXAA-G were 14.2 and 24 ng/ml, respectively. The validated HPLC methods were applied to examine the epithelial transport of DMXAA and DMXAA-G by Caco-2 monolayers. The permeability coefficient (Papp) values (overall mean ± S.D., n = 3-9) of DMXAA over 10-500 μM were independent of concentration for both apical (AP) to basolateral (BL) (4.0 ± 0.4 × 10-5 cm/s) and BL-AP (4.3 ± 0.5 × 10-5 cm/s) transport, and of similar magnitude in either direction, with net efflux ratio (Rnet) values of 1-1.3. However, the Papp values for the BL to AP transport of DMXAA-G were significantly greater than those for the AP to BL transport, with Rnet values of 17.6, 6.7 and 4.5 at 50, 100 and 200 μM, respectively. Further studies showed that the transport of DMXAA-G was Na+- and energy-dependent, and inhibited by MK-571 [a multidrug resistance associated protein (MRP) 1/2 inhibitor], but not by verapamil and probenecid. These data indicate that the HPLC methods for the determination of DMXAA and DMXAA-G in the transport buffer were simple and reliable, and the methods have been applied to the transport study of both compounds by Caco-2 monolayers. DMXAA across Caco-2 monolayers was through a passive transcellular process, whereas the transport of DMXAA-G was mediated by MRP1/2. © 2004 Elsevier B.V. All rights reserved.
Source Title: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
URI: http://scholarbank.nus.edu.sg/handle/10635/105808
ISSN: 15700232
DOI: 10.1016/j.jchromb.2004.06.009
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