The determination of oral bioavailability is a critical step in early phase drug development. In part, the ability to predict whether a drug will be effectively transported across the gastrointestinal mucosa can be estimated from the physicochemical properties of the compound. Currently, the Caco-2 human colon carcinoma cell line is often used by the pharmaceutical industry to evaluate intestinal absorption of drugs. The purpose of the present study was to investigate the membrane transport mechanism of CZ48, a hydrated C20-propionate ester of Camptothecin (CPT), in the Caco-2 cell culture model, in order to understand the possible role of membrane transporters on its oral bioavailability and disposition. Caco-2 cells were grown onto Millicell™ to form monolayers. Directional transport of CZ48 and CPT was determined. The results indicated that apical (AP) to basolateral (BL) transport of CZ48 and CPT was distinctively different from BL to AP transport, with AP to BL transport surpassing the BL to AP transport. The ratio of BL-AP/AP-BL transport rate was 0.36 and 3.0 for CZ48 and CPT at the concentration of 5µM, respectively. The results also showed that AP to BL permeability of CZ48 was ten times lower than CPT, but the accumulation of CZ48 in intact cells was higher than CPT (0.67 and 0.49 nmol, respectively). In conclusion, the p-glycoprotein may be involved in the transepithelial transport of CPT. An additional carrier mechanism may be involved in the AP uptake of CZ48, since Apical transport of CZ48 in the Caco-2 cells is mediated, at least in part, by uptake of a nucleic bases into cells via an nucleobase transporter.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3547.