Long-lasting inhibitory effects of saquinavir and ritonavir on OATP1B1-mediated uptake

J Pharm Sci. 2013 Sep;102(9):3427-35. doi: 10.1002/jps.23477. Epub 2013 Feb 25.


Previously, we reported a long-lasting inhibition of transport mediated by organic anion-transporting polypeptides (OATPs) in humans and rats by cyclosporin A (CsA). In the present study, we examined the effects of several other compounds on OATP1B1-mediated transport, with a focus on long-lasting inhibition. Effects of coincubation, preincubation, or preincubation plus coincubation of 12 compounds on uptake of estrone 3-sulfate (E1 S) in OATP1B1-expressing HEK293T cells were examined. The OATP1B1 inhibitors used in the present study inhibited OATP1B1-mediated uptake of E1 S in a concentration-dependent manner. Among them, saquinavir and ritonavir in addition to CsA exhibited long-lasting inhibitory effects on OATP1B1-mediated transport of E1 S at ≥ 5 and 25 μM, respectively, even after they were washed out from the incubation buffer. After preincubation with saquinavir, its inhibitory effect on OATP1B1 remained for at least 6 h, whereas the effect of ritonavir did not remain. Protein expression of OATP1B1 was not altered by preincubation with 25 μM saquinavir or ritonavir. The present study firstly showed that saquinavir and ritonavir as well as CsA have long-lasting inhibitory effects on OATP1B1. But, at plasma unbound concentrations of saquinavir and ritonavir in clinical situations, they may not cause long-lasting inhibition of OATP1B1.

Keywords: drug interactions; drug transport; hepatic transport; organic anion-transporting polypeptide transporters; pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport / drug effects
  • Estrone / analogs & derivatives*
  • Estrone / metabolism
  • Estrone / pharmacokinetics
  • Gene Expression / drug effects
  • HEK293 Cells
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters / antagonists & inhibitors*
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism*
  • Ritonavir / pharmacology*
  • Saquinavir / pharmacology*


  • HIV Protease Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • SLCO1B1 protein, human
  • Estrone
  • Saquinavir
  • Ritonavir
  • estrone sulfate