The potential of the organic anion transporting polypeptides 1A2 (OATP1A2) or 2B1 (OATP2B1) to transport NOV123 (a proprietary compound) was examined using mammalian cells either transiently express OATP1A2 or stably express OATP2B1. These investigations were done to provide a mechanistic explanation for the apparent reduction in the systemic bioavailability of NOV123 upon oral administration with grapefruit juice. In vitro transport activity was evaluated by comparing the uptake of [14C]NOV123 or the positive control substrates, [3H]fexofenadine (OATP1A2) or [3H]estrone-3-sulfate (OATP2B1) into OATP-expressing cells to that into control cells. Under these assay conditions, NOV123 was found to be a substrate for OATP1A2 but not OATP2B1. In the absence of transport inhibitors, [14C]NOV123 (10 µM) uptake into OATP1A2-expressing cells was 2.7-fold higher than that in control cells following the 15 min uptake assay. Moreover, the accumulation of [14C]NOV123 or the positive control substrate [3H]fexofenadine were reduced in the presence of the positive control OATP1A2 inhibitor verapamil. In contrast, [14C]NOV123 accumulation OATP2B1-expressing cells was essentially the same as that into control cells. Also examined in this study was the potential for naringin (a flavonoid component of grapefruit juice) to inhibit the transport activity of OATP1A2. Naringin was found to inhibit OATP1A2-mediated NOV123 or fexofenadine transport by 86-89%, at the highest concentration tested (1000 µM). The estimated IC50 values of OATP1A2-mediated NOV123 or fexofenadine transport inhibition by naringin were 75.5 ± 11.6 μM and 24.2 ± 2.0 μM, respectively. These IC50 values are within the concentration range of naringin found in grapefruit juice. In conclusion, NOV123 was shown to be a substrate of human OATP1A2 but not OATP2B1. Naringin, a flavonoid component of grapefruit juice inhibited OATP1A2 activity and thus may provide a mechanistic explanation for the reduced exposure to NOV123 in vivo when co-administered with grapefruit juice.