inhibitory effect of clemastine on p-glycoprotein expression and function: an in vitro and in situ study

objective(s):transporters have an important role in pharmacokinetics of drugs. inhibition or induction of drug transporters activity can affect drug absorption, safety, and efficacy. p-glycoprotein (p-gp) is the most important membrane transporter that is responsible for active efflux of drugs. it is important to understand which drugs are substrates, inhibitors, or inducers of p-gp to minimize or avoid unwanted interactions. the aim of this study was to investigate the effects of clemastine on the expression and function of p-gp. materials and methods: the effect of clemastine on p-gp function and expression was evaluated in vitro byrhodamine-123 (rho123) efflux assay in caco-2 cells and western blot analysis. rat in situ single pass intestinal permeability model was used to investigate the clemastine effect on digoxin peff, as a known p-gp substrate. digoxin levels in intestinal perfusates were assayed by high performance liquid chromatography (hplc) method. results:the caco-2 intracellular accumulation of rho123 in clemastine and verapamil treated cells was 90.8 ± 9.8 and 420.6±25.4 pg/mg protein, respectively which was significantly higher than that in control cells (50.2±6.0; p<0.05). immunoblotting results indicated that clemastine decreased expression of p-gp in caco-2 cells in vitro. more over effective intestinal permeability (peff) of digoxin in the presence of clemastine, was significantly increased compare to control group. conclusion: findings of our study suggested dose dependent p-gp inhibition activity for clemastine               in vitro and in situ. therefore co-administration of clemastine with p-gp substrates may result in unwanted interactions and side effects.