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OCTN1 was first cloned in 1997 from fetal liver tissue and found to influx the prototypical cation, TEA, in a saturable, pH‐sensitive manner (K _m = 436 μM) [80]. In contrast to OCTs, OCTNs have a preference for zwitterions, especially carnitine and ergothioneine. Multiple methods of substrate transport have been identified, including cation/proton exchange, cation uniport, and both sodium‐dependent and sodium‐independent zwitterion transport. A proposed nucleotide binding site is present on the intracellular side of OCTNs, which may stimulate transport of some substrates (i.e., TEA). OCTN1 substrates include the prototypical cation TEA, zwitterions (e.g., ergothioneine, acetylcholine, carnitine), and a number of drugs, including quinidine, verapamil, ipratropium, amisulpride, sulpiride, gabapentin, cytarabine, and ethambutol (Table 2.2). OCTN1 has the highest affinity for ergothioneine with a K _m of 21 μM and transports the compound in a sodium‐dependent fashion [2]. In vitro, OCTN1 is inhibited by over 30 compounds, both endogenous and exogenous. Some of the most potent inhibitors appear to be lidocaine (K _i = 0.83 μM), verapamil (K _i = 8.38 μM), ergothioneine (K _i = 9 μM), cobicistat (IC₅₀ = 2.5 μM), carnitine (K _i = 24 μM), and imatinib (IC₅₀ = 31 μM). In humans, no clinical drug–drug interactions have been documented for OCTN1 to date. However, it has been suggested that OCTN1‐mediated secretion of some cationic and zwitterionic substrates may contribute to interindividual variation in drug response [81].

Genetic variants in OCTN1 can alter affinity for substrates and inhibitors, as illustrated by the common polymorphism, p.L503F, which has a higher affinity for xenobiotics but a decreased affinity for carnitine compared to the reference transporter [2]. The p.L503F variant also appears to influence drug excretion in vivo, as evidenced by altered renal clearance of gabapentin, detailed below.