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

To investigate whether Conjugated Estrogens (CEs) as a potential drug with medium or high permeability. Effective permeability (P-eff) of CEs was studied in rat in situ single-pass intestinal perfusions (SPIP) model and apparent permeability (P-app) in Caco-2 cell monolayers model. Atenolol served as a standard reference for the medium of P-eff and P-app. 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 P-eff 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, P-app 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 mu g/ml) and time points (from 15 to 120 min). CEs at the concentration of 200 mu g/ml exhibited higher P-app at secretive direction (BL-AP) compared to that at AP-BL direction [(0.64 +/- 0.16 vs. 0.25 +/- 0.02) x 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 P-eff and P-app) 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.

Automated summary

The study investigated the permeability of Conjugated Estrogens (CEs) as a potential drug using rat intestinal perfusion and cell monolayer models. The results showed that CEs had similar permeability to a reference drug and that their permeability was time- and concentration-dependent. P-gp was found to be involved in the transport of CEs. Overall, CEs can be considered as a drug with moderate permeability.