PT  - JOURNAL ARTICLE
AU  - Zhang, Lei
AU  - Gorset, Wenche
AU  - Washington, Carla B.
AU  - Blaschke, Terrence F.
AU  - Kroetz, Deanna L.
AU  - Giacomini, Kathleen M.
TI  - Interactions of HIV Protease Inhibitors with a Human Organic Cation Transporter in a Mammalian Expression System
DP  - 2000 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 329--334
VI  - 28
IP  - 3
4099  - http://dmd.aspetjournals.org/content/28/3/329.short
4100  - http://dmd.aspetjournals.org/content/28/3/329.full
SO  - Drug Metab Dispos2000 Mar 01; 28
AB  - 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, [14C]tetraethylammonium (TEA), under different experimental conditions. In cis-inhibition studies, all of the HIV protease inhibitors tested, i.e., indinavir (IC50 of 62 μM), nelfinavir (IC50 of 22 μM), ritonavir (IC50 of 5.2 μM), and saquinavir (IC50 of 8.3 μM) inhibited TEA uptake in HeLa cells expressing hOCT1. However, none of the HIV protease inhibitorstrans-stimulated [14C]TEA uptake, suggesting that they are poorly translocated by hOCT1. Nelfinavir, ritonavir, and saquinavir demonstrated an apparent “trans-inhibition” effect. No enhanced uptake of [14C]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. The American Society for Pharmacology and Experimental Therapeutics