Dose dependency in the oral bioavailability of an organic cation model, tributylmethyl ammonium (TBuMA), in rats: Association with the saturation of efflux by the P-gp system on the apical membrane of the intestinal epithelium

The oral bioavailability of tributylmethyl ammonium (TBuMA), an organic cation (OC), exhibited a dose-dependency (i.e., 17, 27, and 35% at doses of 0.4, 4, or 12 µmol/kg, respectively) in the rat. Relevant mechanisms were investigated in the present study by estimating the mucosal to serosal (m-s) and serosal to mucosal (s-m) transport of TBuMA across the rat ileum in an Ussing chamber experiment. The m-s permeability rapidly increased with TBuMA concentration in the mucosal side, and then becoming constant at high TBuMA concentrations. Various studies, including temperature- and potential-dependency and inhibition experiments, revealed that carrier-mediated transport mechanisms (most likely OCT1, OCT3, and P-gp) are involved in the s-m transport of TBuMA, and the saturation of the transport at higher concentrations is responsible for the concentration-dependency in the m-s permeability or dose-dependency of the bioavailability of TBuMA. A nonlinear regression of the m-s transport, based on the assumption of a mixed process of linear diffusion and saturable efflux, exhibited a clearance (CLlinear) of 0.343 µL/min/cm2 for the passive diffusion, and an apparent Km of 241 µM for the saturable process. The Km value is consistent with the concentration range in the intestine which is expected to be achieved after the oral dosing of TBuMA at a dose of 0.4 µmol/kg (i.e., 68∼185 µM). Interestingly, the m-s transport of TBuMA was increased by the presence of P-gp substrates or inhibitors in the mucosal side, but not by the mucosal presence of OCT substrates or inhibitors, suggesting that only efflux transport systems on the apical membrane (e.g., P-gp), but not those on the serosal membrane (e.g., OCT1 and OCT3), of the intestinal epithelial cells, are involved in the dose-dependency or concentration dependency. A similar relationship seems likely for drugs that are substrates of efflux transporters on the apical membrane of the intestinal epithelium. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association.