Abstract
The intestinal absorptive characteristics and the efflux mechanisms of 9-nitrocamptothecin (9-NC), a novel water-insoluble camptothecin (CPT) derivative, were investigated. The Caco-2 cells and the everted gut sacs were used as models of the intestinal mucosa to assess transepithelial transport of 9-NC. The determination of 9-NC was performed by HPLC. In the Caco-2 cells, the absorptive transport of 9-NC was pH dependent and the transport was enhanced at weakly acidic pH on the apical side. No concentration dependence and saturation were observed for the absorptive transport of 9-NC at concentrations up to 250 μM, while secretory transport were concentration dependent and saturable process ( K m was 49.8±1.2 μM, V max was 38.28±0.8 ng/cm 2/min). In the presence of verapamil (100 μM) and CsA (10 μM), potent inhibitors of P-glyprotein (P-gp)/MRP2 (cMOAT), the P app BL-AP / P app AP-BL ratio was decreased from 3.4 to 1.4 and 1.3, respectively, and permeation of apical to basolateral was enhanced approximately two-fold. In the everted gut sacs, the absorption of 9-NC was passive diffusion and had no significant difference in different gut regions. Adding verapamil in the everted gut sacs over a concentration ranging from 10 to 100 μM, the absorption of 9-NC was significantly enhanced, especially more markedly in lower small intestine ( P<0.05). Overall, the current study suggests that pH and efflux transporters are capable of mediating the absorption and efflux of 9-NC, and they may play significant roles in limiting the oral absorption of 9-NC.
Published Version
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