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In vitro, hOCTN2 is multi‐specific and has been shown to transport a number of endogenous compounds and xenobiotics [2]. Primarily, OCTN2 is a sodium‐dependent high‐affinity L‐carnitine transporter with a K _m of 4 μM. To a lesser extent, OCTN2 transports some short‐chain acylcarnitines, including acetyl‐L‐carnitine and the drug metabolites pivaloylcarnitine and valproylcarnitine. OCTN2 transports the prototypical cation, TEA, in a sodium‐independent manner. Other substrates of OCTN2 include drugs ipratropium, mildronate, amisulpride, sulpiride, etoposide, ethambutol, cephaloridine, quinidine, and verapamil (Table 2.2). In vitro, many approved drugs act as inhibitors of OCTN2. Transport of L‐carnitine is inhibited by β‐lactam antibiotics including cefepime, cefoselis, cephaloridine, cefuroxime, cephalexin, and cefazolin with varying IC₅₀ values, likely attributed to the presence of a quaternary amine functional group similar to carnitine. Other strong inhibitors span many drug classes, including cardiac drugs verapamil, quinidine, and amiodarone, proton‐pump inhibitors such as omeprazole, and anticancer agents including tamoxifen, gefitinib, and cedirinib, among others.

In vivo, OCTN2 has not been reported as a target for drug–drug interactions to date. However, multiple drugs have been observed to cause carnitine deficiency through various mechanisms. Administration of the anticonvulsant valproic acid and the antibiotic pivalic acid causes reduced plasma carnitine levels and, in some cases, clinically relevant carnitine deficiency. Multiple mechanisms have been proposed. One possibility is that valproate and pivalate directly inhibit the binding pocket for carnitine in OCTN2. Other studies have suggested that rather than inhibit OCTN2 directly, these drugs form carnitine conjugates and are likely effluxed out of the kidney with poor reabsorption, resulting in carnitine wasting and depletion. Alternatively, the valproyl‐ and pivaloyl‐carnitine esters could block reabsorption of free carnitine at OCTN2. Regardless of mechanism, these cases of drug‐induced carnitine deficiency have been fatal in patients with carnitine transporter deficiency who already have reduced systemic carnitine levels.

In recent years, OCTN2 has become a target of drug delivery optimization strategies. Multiple properties make it an attractive drug target. First, it is theorized to increase oral bioavailability of targeted drugs due to high expression in the small intestine. Second, it has the potential to increase blood–brain barrier permeability of substrates due to expression at the BBB. Third, it allows for the targeting of drugs to the kidney. And fourth, it has been hypothesized to increase delivery of asthma therapeutics to the lung [90]. Multiple carnitine‐conjugated prodrugs have been developed, including butyrate used in treatment for gut inflammation, nepotic acid used to treat seizures, and the chemotherapeutic drug, gemcitabine. Carnitine‐conjugated gemcitabine exhibits 5‐fold bioavailability over gemcitabine alone. In addition, nanoparticles are being explored for targeted delivery via OCTN2 for other cancer drugs like paclitaxel.