Читать книгу Drug Transporters - Группа авторов - Страница 39

The renal proximal tubule is the primary site for the secretion of organic cations including many basic drugs. Several endogenous organic cations have been shown to be actively secreted by proximal tubule including N1‐methylnicotinamide, choline, histamine, and thiamine. Human OCT2 transports multiple substrates in common with hOCT1 (Table 2.2). For example, hOCT2 transports MPP⁺, TEA, quinine, and metformin with similar affinity [1]. However, other substrates (i.e., choline, acetylcholine, dopamine, epinephrine, serotonin, cisplatin) have higher affinity for hOCT2 compared with hOCT1 [1]. In addition, the potency of inhibitors can be dependent on substrate used in the in vitro assay [2]. The IC₅₀ values for inhibition of MPP⁺ transport by nine structurally distinct organic cations are 9‐fold greater than those for inhibition of metformin transport. OCT2‐mediated MPP⁺ transport is relatively insensitive to inhibition as determined by inhibitory profiles produced for more than 400 structurally distinct inhibitors against OCT2‐mediated transport of MPP⁺, metformin, cimetidine, TEA, ASP⁺, and the fluorescent organic cation, N,N,N‐trimethyl‐2‐[methyl(7‐nitrobenzo[c][l,2,5]oxadiazol‐4‐yl)amino]ethanaminium (NBD‐MTMA). Kinetic studies reveal that MPP⁺ interacts with multiple OCT2 sites. Whereas metformin’s inhibition of MPP⁺ transport is competitive (i.e., an increase in the apparent K _m value for MPP⁺ transport while having no effect on V _max), MPP⁺ exerts a “mixed‐type” inhibition of metformin transport (i.e., both an increase in the apparent K _m value and a decrease in V _max) [40]. Overall, metformin appears to be a comparatively representative OCT2 substrate for both in vitro and clinical use.