Abstract

The antiparasitic activity of aromatic diamidine drugs, pentamidine and furamidine, depends on their entry into the pathogenic protozoa via membrane transporters. However, no such diamidine transporter has been identified in mammalian cells. The goal of this study is to investigate whether these dicationic drugs are substrates for human organic cation transporters (hOCTs, solute carrier family 22A1–3) and whether hOCTs play a role in their tissue distribution, elimination, and toxicity. Inhibitory and substrate activities of pentamidine and furamidine were studied in stably transfected Chinese hamster ovary (CHO) cells. The results of [³H]1-methyl-4-phenylpyridinium uptake study showed that pentamidine is a potent inhibitor for all three OCT isoforms (IC₅₀ < 20 μM), whereas furamidine is a potent inhibitor for hOCT1 and hOCT3 (IC₅₀ < 21 μM) but a less potent inhibitor for hOCT2 (IC₅₀ = 189.2 μM). Both diamidines are good substrates for hOCT1 (K_m = 36.4 and 6.1 μM, respectively), but neither is a substrate for hOCT2 or hOCT3. The cytotoxicity of pentamidine and furamidine was 4.4- and 9.3-fold greater, respectively, in CHO-hOCT1 cells compared with the mock cells. Ranitidine, an hOCT1 inhibitor, reversed this hOCT1-mediated potentiation of cytotoxicity. This is the first finding that dicationic drugs, such as pentamidine and furamidine, are substrates for hOCT1. In humans, aromatic diamidines are primarily eliminated in the bile but are distributed and cause toxicity in both liver and kidney. These transporters may play important roles in the disposition of aromatic diamidines in humans, as well as resultant drug-drug interactions and toxicity involving diamidine drugs.