Transport of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid and its acyl glucuronide by human intestinal Caco-2 cells

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent cytokine inducer, exhibited marked antitumor activity when given as multiple oral doses in mice. The aim of this study was to examine the transport of DMXAA and its acyl glucuronide (DMXAA-G) using the human Caco-2 cells. DMXAA was minimally metabolized by Caco-2 cells and both DMXAA and DMXAA-G were taken up to a minor extent by the cells. The permeability coefficient (P_app) values of DMXAA over 10–500 μM were 4 × 10⁻⁵ cm/s to 4.3 × 10⁻⁵ cm/s for both apical (AP) to basolateral (BL) and BL-AP transport, while the P_app values for the BL to AP flux of DMXAA-G were significantly greater than those for the AP to BL flux, with R_net values of 4.5–17.6 over 50–200 μM. The BL to AP active efflux of DMXAA-G followed Michaelis-Menten kinetics, with a K_m of 83.5 ± 5.5 μM, and V_max of 0.022 ± 0.001 nmol/min. The flux of DMXAA-G was energy and Na⁺-dependent and MK-571 significantly (P < 0.05) inhibited its BL to AP flux, with an estimated K_i of 130 μM. These data indicate that the transport of DMXAA across Caco-2 monolayers was through a passive process, whereas the transport of DMXAA-G was mediated by MRP1/2.