Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells

J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Nov 1;19(3):203-9. doi: 10.1097/00042560-199811010-00001.


The anti-HIV protease inhibitors represent a new class of agents for treatment of HIV infection. Saquinavir, ritonavir, indinavir, and nelfinavir are the first drugs approved in this class and significantly reduce HIV RNA copy number with minimal adverse effects. They are all substrates of cytochrome P450 3A4, and are incompletely bioavailable. The drug transporting protein, P-glycoprotein (P-gp), which is highly expressed in the intestinal mucosa, could be responsible for the low oral bioavailability of these and other drugs which are substrates for this transporter. To determine whether these protease inhibitors are modulators of P-gp, we studied them in cell lines which do and do not express P-gp. Saquinavir, ritonavir and nelfinavir significantly inhibited the efflux of [3H]paclitaxel and [3H]vinblastine in P-gp-positive cells, resulting in an increase in intracellular accumulation of these drugs. However, similar concentrations of indinavir did not affect the accumulation of these anticancer agents. In photoaffinity labeling studies, saquinavir and ritonavir displaced [3H]azidopine, a substrate for P-gp, in a dose-dependent manner. These data suggest that saquinavir, ritonavir, and nelfinavir are inhibitors and possibly substrates of P-gp. Because saquinavir has a low bioavailability, its interaction with P-gp may be involved in limiting its absorption.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Anti-HIV Agents / metabolism*
  • Anti-HIV Agents / toxicity
  • Antibiotics, Antineoplastic / metabolism
  • Antibiotics, Antineoplastic / toxicity
  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / toxicity
  • Biological Availability
  • Cell Survival / drug effects
  • Daunorubicin / metabolism
  • Daunorubicin / toxicity
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Female
  • HIV Protease Inhibitors / metabolism*
  • HIV Protease Inhibitors / toxicity
  • Humans
  • Indinavir / metabolism
  • Indinavir / toxicity
  • Leukemia, Erythroblastic, Acute
  • Nelfinavir / metabolism
  • Nelfinavir / toxicity
  • Paclitaxel / metabolism
  • Paclitaxel / toxicity
  • Ritonavir / metabolism
  • Ritonavir / toxicity
  • Saquinavir / metabolism
  • Saquinavir / toxicity
  • Sarcoma
  • Tumor Cells, Cultured
  • Uterine Neoplasms
  • Vinblastine / metabolism
  • Vinblastine / toxicity


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-HIV Agents
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • HIV Protease Inhibitors
  • Vinblastine
  • Indinavir
  • Nelfinavir
  • Saquinavir
  • Ritonavir
  • Paclitaxel
  • Daunorubicin