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

Pharm Res. 2004 Sep;21(9):1686-91. doi: 10.1023/b:pham.0000041466.84653.8c.


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 microM.

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 -25-50 microM) 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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Atorvastatin
  • Biological Transport, Active
  • Cell Line
  • Drug Interactions
  • Heptanoic Acids / metabolism*
  • Heptanoic Acids / pharmacology
  • Humans
  • Hypolipidemic Agents / metabolism*
  • Pyrroles / metabolism*
  • Pyrroles / pharmacology
  • Ritonavir / metabolism
  • Simvastatin / analogs & derivatives*
  • Simvastatin / metabolism*
  • Simvastatin / pharmacology
  • Time Factors


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Heptanoic Acids
  • Hypolipidemic Agents
  • Pyrroles
  • simvastatin acid
  • Atorvastatin
  • Simvastatin
  • Ritonavir