Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system

Recently, we cloned a human organic cation transporter, hOCT1, which is exp ressed primarily in the liver. hOCT1 plays an important role in the cellula r uptake and elimination of various xenobiotics including therapeutically i mportant drugs. HIV protease inhibitors are a new class of therapeutic agen ts. The purpose of this study was to elucidate the interactions of HIV prot ease inhibitors with hOCT1 and to determine whether hOCT1 is involved in th e elimination of these compounds. We studied the interactions of HIV protea se inhibitors with hOCT1 in a transiently transfected human cell line, HeLa . Uptake studies were carried out 40 h post-transfection using the radiolab eled model organic cation, [C-14]tetraethylammonium (TEA), under different experimental conditions. In cis-inhibition studies, all of the HIV protease inhibitors tested, i.e., indinavir (IC50 of 62 mu M), nelfinavir (IC50 of 22 mu M), ritonavir (IC50 of 5.2 mu M), and saquinavir (IC50 of 8.3 mu M) i nhibited TEA uptake in HeLa cells expressing hOCT1. However, none of the HI V protease inhibitors trans-stimulated [C-14]TEA uptake, suggesting that th ey are poorly translocated by hOCT1. Nelfinavir, ritonavir, and saquinavir demonstrated an apparent "trans-inhibition" effect. No enhanced uptake of [ C-14]saquinavir was observed in hOCT1 DNA-transfected cells versus empty ve ctor-transfected cells. These data suggest that HIV protease inhibitors are potent inhibitors, but poor substrates, of hOCT1. Some HIV protease inhibi tors may potently inhibit the uptake and elimination of cationic drugs that are substrates for hOCT1, leading to potential drug-drug interactions. Oth er transporters, e.g., MDR1 and MRP1, in HIV-targeted cells may control the intracellular concentrations of HIV protease inhibitors.