Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin

Purpose. In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin (SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug interactions. Methods. P-gp mediated efflux of SV, SVA, and AVA was determined by directional transport across monolayers of LLC-PK1 cells and LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50 muM. Results. Directional transport studies showed insignificant P-gp mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA, respectively. Inhibition studies did not show the same trend as the transport studies with SV and AVA inhibiting P-gp (IC50 similar to25-50 muM) but SVA not showing any inhibition of P-gp. Conclusions. The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.