Pharmaceutical Research

, Volume 21, Issue 9, pp 1686–1691

Interactions of Human P-glycoprotein with Simvastatin, Simvastatin Acid, and Atorvastatin

  • Jerome H. Hochman
  • Nicole Pudvah
  • Julia Qiu
  • Masayo Yamazaki
  • Cuyue Tang
  • Jiunn H. Lin
  • Thomayant Prueksaritanont
Article

DOI: 10.1023/B:PHAM.0000041466.84653.8c

Cite this article as:
Hochman, J.H., Pudvah, N., Qiu, J. et al. Pharm Res (2004) 21: 1686. doi:10.1023/B:PHAM.0000041466.84653.8c

Abstract

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 μM.

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 μM) 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.

P-glycoproteinsimvastatinatorvastatinHMG-CoAreductase inhibitordrug interactions

Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • Jerome H. Hochman
    • 1
  • Nicole Pudvah
    • 1
  • Julia Qiu
    • 1
  • Masayo Yamazaki
    • 1
  • Cuyue Tang
    • 1
  • Jiunn H. Lin
    • 1
  • Thomayant Prueksaritanont
    • 1
  1. 1.Department of Drug MetabolismMerck Research LaboratoriesWest PointUSA