title: Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system.
abstract: Recently, we cloned a human organic cation transporter, hOCT1, which is expressed primarily in the liver. hOCT1 plays an important role in the cellular uptake and elimination of various xenobiotics including therapeutically important drugs. HIV protease inhibitors are a new class of therapeutic agents. The purpose of this study was to elucidate the interactions of HIV protease inhibitors with hOCT1 and to determine whether hOCT1 is involved in the elimination of these compounds. We studied the interactions of HIV protease inhibitors with hOCT1 in a transiently transfected human cell line, HeLa. Uptake studies were carried out 40 h post-transfection using the radiolabeled model organic cation, [(14)C]tetraethylammonium (TEA), under different experimental conditions. In cis-inhibition studies, all of the HIV protease inhibitors tested, i.e., indinavir (IC(50) of 62 microM), nelfinavir (IC(50) of 22 microM), ritonavir (IC(50) of 5.2 microM), and saquinavir (IC(50) of 8.3 microM) inhibited TEA uptake in HeLa cells expressing hOCT1. However, none of the HIV protease inhibitors trans-stimulated [(14)C]TEA uptake, suggesting that they are poorly translocated by hOCT1. Nelfinavir, ritonavir, and saquinavir demonstrated an apparent "trans-inhibition" effect. No enhanced uptake of [(14)C]saquinavir was observed in hOCT1 DNA-transfected cells versus empty vector-transfected cells. These data suggest that HIV protease inhibitors are potent inhibitors, but poor substrates, of hOCT1. Some HIV protease inhibitors may potently inhibit the uptake and elimination of cationic drugs that are substrates for hOCT1, leading to potential drug-drug interactions. Other transporters, e.g., MDR1 and MRP1, in HIV-targeted cells may control the intracellular concentrations of HIV protease inhibitors.
authors.affiliation: Department of Biopharmaceutical Sciences, University of California, San Francisco, California 94143-0446, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Gorset
authors.forename: C B
authors.initials: CB
authors.lastname: Washington
authors.forename: T F
authors.initials: TF
authors.lastname: Blaschke
authors.forename: D L
authors.initials: DL
authors.lastname: Kroetz
authors.forename: K M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D008565:Membrane Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019888:Nelfinavir / Q000494:pharmacology; D027702:Organic Cation Transporter 1; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D019789:Tetraethylammonium / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D017320:HIV Protease Inhibitors; D019469:Indinavir; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019888:Nelfinavir; D027702:Organic Cation Transporter 1; D012333:RNA, Messenger; D019438:Ritonavir; D019258:Saquinavir; D019789:Tetraethylammonium