Characterization of efflux transport of the PDE5 inhibitors, vardenafil and sildenafil

J Pharm Pharmacol. 2012 Aug;64(8):1074-83. doi: 10.1111/j.2042-7158.2012.01498.x. Epub 2012 Mar 16.

Abstract

Objectives: We aimed to characterize the efflux transport properties of vardenafil and sildenafil, and to compare the kinetics of these compounds via efflux transporters such as P-gp, BCRP and MRP2.

Methods: We measured the basal-to-apical and apical-to-basal transport of vardenafil and sildenafil within the concentration range of 1-100 µm using MDCKII cells overexpressing P-gp, BCRP and MRP2, and Caco-2 cells.

Key findings: Vardenafil had a much greater basal-to-apical than apical-to-basal transport rate in MDCKII cells overexpressing P-gp, BCRP and MRP2. Sildenafil showed P-gp- and BCRP-mediated efflux transport, but did not seem to be pumped out via MRP2 transporters. Consequently, the absorptive transport of vardenafil and sildenafil in Caco-2 cells increased linearly over the concentration range of 1-100 µm, whereas the secretory transport of these drugs was saturable and inhibited by the presence of specific inhibitors of P-gp and BCRP. MK571, a representative MRP2 inhibitor, inhibited the basal-to-apical transport of vardenafil, but not of sildenafil.

Conclusion: The involvement of P-gp, BCRP and MRP2 for vardenafil and the involvement of P-gp and BCRP for sildenafil in the secretory transport with linear absorptive transport may contribute to the limited intestinal absorption of these drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism*
  • Biological Transport
  • Caco-2 Cells
  • Humans
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics*
  • Intestinal Absorption
  • Leukotriene Antagonists / pharmacology
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Neoplasm Proteins / metabolism*
  • Phosphodiesterase 5 Inhibitors / metabolism
  • Phosphodiesterase 5 Inhibitors / pharmacokinetics*
  • Piperazines / metabolism
  • Piperazines / pharmacokinetics*
  • Propionates / pharmacology
  • Purines / metabolism
  • Purines / pharmacokinetics
  • Quinolines / pharmacology
  • Sildenafil Citrate
  • Sulfones / metabolism
  • Sulfones / pharmacokinetics*
  • Triazines / metabolism
  • Triazines / pharmacokinetics
  • Vardenafil Dihydrochloride

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Imidazoles
  • Leukotriene Antagonists
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Propionates
  • Purines
  • Quinolines
  • Sulfones
  • Triazines
  • multidrug resistance-associated protein 2
  • Vardenafil Dihydrochloride
  • verlukast
  • Sildenafil Citrate