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Abstract:

To characterize the intestinal absorption of TMC114 and assess possible role of P-glycoprotein (P-gp).Caco-2 cells, grown for 21 days on cell culture, were used. 14C-TMC114 was applied either to the apical or basolateral side of the monolayer to measure absorptive and secretary transport. The role of P-gp in TMC114 transport was assessed using P-gp inhibitors verapamil and ritonavir (100 µM). Possible inhibition of P-gp by TMC114 or ritonavir (up to 100 µM) was also studied using taxol as a substrate.Transepithelial permeability of TMC114 was intermediate to high when compared with reference compounds for low, medium and high permeation. TMC114 permeation was highly polarized initially (0-15 min) with efflux ratio (ER=secretory/absorptive permeation) values of up to 17. At later time points (15-45-60 min), TMC114 transport was moderately polarized (ER up to 6). Both transport polarity and bi-directional transport rates were strongly concentration-dependent, with initial ER values decreasing from about 17 to 3 for initial TMC114 concentrations of 3 and 300 µM, respectively. Co-incubation with verapamil reduced the ER of TMC114 at 30 µM from 5.4 to 3.1, whereas a more pronounced effect on ER was obtained with ritonavir (ER=2.1). Bi-directional transport experiments with the P-gp substrate taxol demonstrated that TMC114 has P-gp inhibitory property (IC50 32.9 µM), which was less pronounced than those of ritonavir (IC50 12.7 µM).While these data support the involvement of an efflux transporter, passive transcellular diffusion is proposed as the predominant mechanism for TMC114 absorption. Given the fact that TMC114 solubility and dissolution rate in the gastrointestinal environment are not limiting factors at the therapeutic dose, it can be concluded that TMC114 will exhibit sufficient membrane permeability to obtain adequate intestinal absorption. One or more efflux transporters are modulating TMC114 permeation, but the impact of these efflux mechanisms is limited at high TMC114 concentrations that are relevant for the in vivo situation (> 100 µM). The present data suggest that TMC114 differs from some other HIV protease inhibitors with regard to impact of efflux transporters on its intestinal absorption.