Comparison of the permeability between conjugated estrogens and atenolol in rat in situ single-pass intestinal perfusions model and in Caco-2 cell monolayers

Abstract

To investigate whether Conjugated Estrogens (CEs) as a potential drug with medium or high permeability. Effective permeability (Peff) of CEs was studied in rat in situ single-pass intestinal perfusions (SPIP) model and apparent permeability (Papp) in Caco-2 cell monolayers model. Atenolol served as a standard reference for the medium of Peff and Papp. Further, the intestinal epithelial permeability of CEs was assessed across Caco-2 cell monolayers in both apical (AP)-basolateral (BL) and BL-AP directions, the effects of time and concentration of CEs and the involvement of P-Glycoprotein (P-gp) in CEs transport were also investigated. Results showed that Peff of CEs and atenolol in two different segments of rat intestine (the jejunum and the ileum) were comparable (P=NS). In Caco-2 cell model, Papp of CEs and atenolol at absorptive (AP-BL) direction were also similar. The transport of CEs was time- and concentration-dependent in the tested concentration range (from 80 to 500 μg/ml) and time points (from 15 to 120 min). CEs at the concentration of 200 μg/ml exhibited higher Papp at secretive direction (BL-AP) compared to that at AP-BL direction [(0.64 ± 0.16 vs. 0.25 ± 0.02) × 10−6 cm/s, P < 0.05]. P-gp inhibitors, verapamil and cyclosporin A, significantly increased passive transport of CEs at absorptive direction but decreased active transport at secretive direction, indicating that CEs is a substrate of P-gp. In summary, as the permeabilities (both Peff and Papp) of CEs and atenolol in SPIP and cell models were comparable, CEs can be considered as a drug with moderate permeability. CEs transport is time- and concentration-dependent and P-gp is able to mediate a CEs efflux.