[44]
3.3.2.2 Platinum Drugs
Platinum‐based anticancer drugs are also substrates of MATE transporters with preference of cisplatin for hMATE1 and rMate1 and oxaliplatin for hMATE2‐K [37, 38]. Treatment of Mate1 knockout mice with cisplatin increased renal platinum accumulation and heightened susceptibility to cisplatin‐induced nephrotoxicity compared with wild‐type mice [39]. Similar results were reported in mice treated with a pharmacological inhibitor of Mate1 [39]. In addition to causing renal damage, platinum‐based drugs are also well known for the ability to cause peripheral neuropathy. Treatment of rats with oxaliplatin and rMate1 siRNA injections increased platinum accumulation in the dorsal root ganglion, as well as the extent of peripheral neuropathy compared with that of rats receiving only oxaliplatin [40]. Taken together, these data point to the ability of Mate transporters to regulate the toxicities associated with platinum drugs.
3.3.2.3 Cardiovascular Drugs
A number of drugs that alter cardiovascular function are substrates for MATE transporters. For example, beta‐adrenergic agonist/antagonist drugs, such as fenoterol, atenolol, nadolol and salbutamol, are substrates for hMATE1 and hMATE2‐K [41, 42]. Notably, transport of these drugs tends to be higher capacity, lower affinity, and with moderate stereoselectivity compared with OCT‐type transporters [41]. Dual expression of hOCT2 and hMATE1 in MDCK cells enabled the transepithelial transport of atenolol compared to control cells [43]. These data suggest that this transporter system is responsible for the renal secretion of atenolol.
3.3.2.4 Alkaloids
Alkaloid drugs are used clinically for their anticholinergic properties for diseases such as chronic obstructive pulmonary disease, asthma, ocular disorders, and gastrointestinal illness. In particular, the quaternary amine derivatives of alkaloids, namely ipratropium and trospium, are transported by MATE transporters. The transcellular transport of ipratropium and trospium is accomplished by hMATE1 in combination with either hOCT1 or hOCT2 in MDCKII cells [44, 45]. These studies may provide insights into the hepatic and/or renal clearance of alkaloid‐type drugs.
3.3.2.5 Paraquat
Paraquat is a divalent cation and herbicide widely used across the globe. It is highly toxic to the kidneys, as well as the liver and lungs. Paraquat is excreted via glomerular filtration and tubular secretion [46]. Renal uptake of paraquat is presumed to occur via OCT2/Oct2 on the basolateral membrane [47]. hMATE1 and rMate1 demonstrate time‐dependent in vitro uptake of paraquat [47]. When expressed in proteoliposomes, hMATE1 is capable of transporting paraquat, but interestingly paraquat/proton exchange is stimulated by inside‐negative membrane potential and inhibited by inside‐positive membrane potential, which contrasts the electroneutral transport observed with prototypical substrates such as TEA [48]. Overexpression of hMATE1 not only enhances paraquat uptake but also heightens cytotoxicity by over 5‐fold compared with control cells [47]. In mice lacking Mate1, paraquat accumulates in plasma, lung, and kidneys to a greater extent than in wild‐type mice [33]. As a result, Mate1‐knockout mice exhibit enhanced susceptibility to paraquat‐induced nephrotoxicity [33]. While paraquat is a unique pesticide whose disposition and toxicity are dependent upon Mate activity, other classes of pesticides appear to have minimal interaction [49].
3.3.2.6 Endogenous Molecules
Endogenous molecules have been identified as substrates of MATE/Mate transporters. For example, the initial development of Mate1 knockout mice confirmed the in vitro evidence that this transporter can efflux creatinine. Baseline levels of creatinine within the blood of Mate1 knockout mice are elevated [32]. N 1‐methyladenosine, which is a metabolite of niacin or nicotinamide, is a substrate of MATE2‐K in vitro [50]. Treatment of mice with a Mate inhibitor increased plasma concentrations of N 1‐methyladenosine in a time‐dependent manner and reduced its overall renal clearance [50]. The cationic neurotransmitter dopamine is also a substrate of hMATE1, hMATE2‐K, and mMate1 in vitro. in vivo, mice lacking mMate1 have reduced urinary excretion of dopamine. Moreover, the ability of renally synthesized dopamine to cause natriuresis and diuresis is absent in Mate1
