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Review ArticleReview Article

Organic Cation Transporters in Health and Disease

Hermann Koepsell
Lynette C. Daws, ASSOCIATE EDITOR
Pharmacological Reviews January 2020, 72 (1) 253-319; DOI: https://doi.org/10.1124/pr.118.015578

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Evolutionary relationships of OCTs of the SLC22 family that belong to the MFS superfamily like GLUT2, and OCTs of the MATE family. The relationships were calculated based on nucleotide sequence. Distance along branches is inversely related to degree of sequence identity.

  • Fig. 2.
    Fig. 2.

    Predicted membrane topology of human OCTs (A) belonging to the SLC22 family and of hMATE1 (B) that belongs to the MATE family of transporters.

  • Fig. 3.
    Fig. 3.

    Views into the modeled outward-open (upper panel) and inward-open (lower panel) binding cleft of rOCT1. Modeling was performed, as described (Popp et al., 2005; Volk et al., 2009). Trp218, Arg440, and Asp475 located within the inner parts of the modeled outward-open and inward-open clefts are indicated.

  • Fig. 4.
    Fig. 4.

    Effects of mutations of amino acids lining the modeled outward-open cleft of rOct1 on MPP binding to low-affinity and high-affinity binding sites. (A) Numbers of MPP molecules per transporter monomer that bind to GFP-fusion proteins with Oct1 WT or the indicated mutants. Binding measurements were performed to fusion proteins that had been reconstituted into nanodiscs, and maximal low-affinity and high-affinity binding was determined. *Significant difference compared with rOCT1. •Significant difference compared with all other rOct variants. (B) Hypothetic model based on the observation that Trp218 (green) and Asp475 (red) are located in neighboring positions in the modeled outward-open cleft and more distant in the modeled inward-open cleft. Arg440 is indicated in blue.

  • Fig. 5.
    Fig. 5.

    Location of OCTs in enterocytes of human small intestine.

  • Fig. 6.
    Fig. 6.

    Location of OCTs in hepatocytes of human liver.

  • Fig. 7.
    Fig. 7.

    Location of OCTs in proximal epithelial cells of human kidney.

  • Fig. 8.
    Fig. 8.

    Location of OCTs in ciliated epithelial cells of human trachea.

  • Fig. 9.
    Fig. 9.

    Location of OCTs in human brain. It has not been resolved whether the depicted OCTs are located in the luminal and/or basal membrane of the small brain vessels.

Tables

  • TABLE 1

    Model substrates of human organic cation transporters

    Charge of major microspecies at pH 7.4 was calculated with program MarvinSketch version 19.3 of ChemAxon (https://chemaxon.com/products/marvin). ASP: Biermann et al., 2006; Grigat et al., 2009; Ahlin et al., 2011; Kido et al., 2011; Wittwer et al., 2013; Chen et al., 2017a; Sandoval et al., 2018, DAPI (4′,6-diamidino-2-phenylindole): Yasujima et al., 2010, 2011, fluoro-L-α-methyltyrosine: Wei et al., 2016, fluoromethylcholine: Visentin et al., 2017b, 2018, MPP: Gorboulev et al., 1997; Zhang et al., 1997; Ohashi et al., 1999; Wu et al., 2000; Bednarczyk et al., 2003; Gründemann et al., 2003; Otsuka et al., 2005; Sata et al., 2005; Masuda et al., 2006; Tanihara et al., 2007; Lee et al., 2009; Zolk et al., 2009a; Astorga et al., 2012; Belzer et al., 2013; Bexten et al., 2015; Lechner et al., 2016; Martínez-Guerrero et al., 2016, NBD-MTMA: Belzer et al., 2013; Martínez-Guerrero and Wright, 2013; Martínez-Guerrero et al., 2016; Sandoval et al., 2018, N-metyl-quinidine: Van Montfoort et al., 2001, rhodamine 123: Jouan et al., 2014; Lechner et al., 2016, TEA: Gorboulev et al., 1997; Zhang et al., 1997; Tamai et al., 1998; Ohashi et al., 2002; Bednarczyk et al., 2003; Peltekova et al., 2004; Bourdet et al., 2005; Otsuka et al., 2005; Masuda et al., 2006; Geier et al., 2007; Tanihara et al., 2007; Umehara et al., 2007; Cheng et al., 2009; Ming et al., 2009; Ohta et al., 2009; Astorga et al., 2012; Belzer et al., 2013; Hendrickx et al., 2013; Sandoval et al., 2018.

    Compound (Charge of Major Microspecies at pH 7.4)Apparent Km (IC50) [µM]
    hOCT1hOCT2hOCT3hOCTN1hOCTN2hMATE1hMATE2-K
    ASP (+) f2.3–2136–42n.t.d.5.8a, 34a
    DAPI (++) f8.9n.t.d.n.t.d.n.t.d.n.t.d.1.1a3.2a
    Fluoro-L-α-methyltyrosine (+−)n.t.d.n.t.d.t
    Fluoromethylcholine (+)t14, 1800t
    MPP (+)15–32 (16)3–20 (3.0)47–83n.t.d.4.4a–100a (22a–54a)3.3a–111a
    NBD-MTMA (++) f8.8, 9.6 (8.3, 64)20,a 105a (67a–112a)
    N-methyl-quinindine (+)20
    Rhodamine 123 (+) f0.54 (0.37)0.61 (62)0.79a10a
    TEA (+)69–229 (216)27–76 (110, 222)(1240–1480)439292, 304220,a 380a (41a)760,a 830a (14a)

    • f, fluorescent; NBD-MTMA, N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]ethanaminium iodide; n.t.d., no transport detected; t, transported.

    • ↵a Uptake measurements performed in presence of an outwardly directed proton gradient; IC50 values are presented in brackets.

  • TABLE 2

    Endogeneous compounds, including metabolites and nontoxic nutrient components that are transported by human organic cation transporters

    Charge of major microspecies at pH 7.4 was calculated with program MarvinSketch of ChemAxon. Acetylcholine: Lips et al., 2005; Pochini et al., 2012, acetyl-L-carnitine: Ohashi et al., 1999, agmatine: Gründemann et al., 2003; Astorga et al., 2012, amoxicillin: Parvez et al., 2018, betaine: Wu et al., 1999; Wagner et al., 2000; Urban et al., 2007, L-carnitine: Tamai et al., 1998; Seth et al., 1999; Yabuuchi et al., 1999; Wagner et al., 2000; Ohashi et al., 2002; Peltekova et al., 2004; Grube et al., 2006; Masuda et al., 2006, D-carnitine: Ohashi et al., 1999; Wagner et al., 2000, choline: Gorboulev et al., 1997; Wu et al., 1999; Wagner et al., 2000; Bednarczyk et al., 2003; Peltekova et al., 2004; Otsuka et al., 2005; Chen et al., 2014; Pochini et al., 2015; Severance et al., 2017; Visentin et al., 2018, creatinine: Urakami et al., 2004; Masuda et al., 2006; Tanihara et al., 2007; Imamura et al., 2011; Astorga et al., 2012; Ciarimboli et al., 2012; Lepist et al., 2014, cyclo(His-Pro): Taubert et al., 2007; Tanihara et al., 2009, 2′deoxycytidine: Drenberg et al., 2017, dopamine: Busch et al., 1998; Bednarczyk et al., 2003; Amphoux et al., 2006; Zolk et al., 2009a; Zhu et al., 2010; Chen et al., 2014, ergothioneine: Gründemann et al., 2005; Grigat et al., 2009; Futatsugi et al., 2016, estrone sulfate: Tanihara et al., 2007; Lechner et al., 2016, epinephrine: Gründemann et al., 1998; Amphoux et al., 2006; Chen et al., 2014, guanidine: Ohashi et al., 1999; Wu et al., 1999, 2000; Urakami et al., 2004; Masuda et al., 2006; Tanihara et al., 2007; Kimura et al., 2009, histamine: Busch et al., 1998; Gründemann et al., 1998; Bednarczyk et al., 2003; Amphoux et al., 2006; Astorga et al., 2012; Chen et al., 2014, 6-β-hydroxycortisol: Imamura et al., 2013, lysine: Wagner et al., 2000, methionine: Wagner et al., 2000, N-1-methylnicotinamide: Gorboulev et al., 1997; Zhang et al., 1998; Wu et al., 1999; Bednarczyk et al., 2003; Peltekova et al., 2004; Masuda et al., 2006; Sakata et al., 2010; Ito et al., 2012a, norepinephrine: Busch et al., 1998; Gründemann et al., 1998; Amphoux et al., 2006; Zolk et al., 2009a; Zhu et al., 2010; Chen et al., 2014; Song et al., 2019, salsolinol: Taubert et al., 2007, serotonin: Busch et al., 1998; Otsuka et al., 2005; Amphoux et al., 2006; Zhu et al., 2010; Astorga et al., 2012; Boxberger et al., 2014; Chen et al., 2014, stachydrine: Gründemann et al., 2005, thiamine: Dutta et al., 1999; Bednarczyk et al., 2003; Masuda et al., 2006; Tanihara et al., 2007; Astorga et al., 2012; Chen et al., 2014; Kato et al., 2014; Lechner et al., 2016, trimethylamine N-oxide: Miyake et al., 2017; Teft et al., 2017, tyramine: Gründemann et al., 1998; Bednarczyk et al., 2003; Chen et al., 2014, quercetin: Lee et al., 2014b.

    Compound (Charge of Major Microspecies at pH 7.4)Km (IC50) [µM]
    hOCT1hOCT2hOCT3hOCTN1hOCTN2hMATE1hMATE2-K
    Acetylcholine (+)(580)1171000
    Acetyl-L-carnitine (+/−)8.5
    Agmatine (++)t (24,000)14002500(54a)(61a)
    Betaine (+/−)tt
    Choline (+)t (3540)210–404t (231)t (>2000)(>5000a)
    Creatinine (+)t1820, 4000 (580)1320n.t.d.n.t.d.>2000 (195a)>2000 (150a)
    Cyclo (His-Pro) (0)65574126
    D-Carnitine (+/−)11, 98
    L-Carnitine (+/−)5713.5–7.7n.t.d.
    2′Deoxycytidine (0)t
    Dopamine (+)t (487)390–1400800.
    Epinephrine (+)t420240
    Ergothioneine (+/−)21, 85n.t.d.
    Estrone 3-sulfate (−)470a850a
    Guanidine (+)(2200, 3030)(6201)n.t.d., n.i.d.2100a4200a
    6-β-Hydroxycortisol (0)tt
    Histamine (+)t (3007)940, 1300180, 220(761a)(775a)
    Lysine (++/−)t
    Methionine (+/−)t
    N-1-methylnicotinamide (0)(1035, 7700)318 (266–1000)(77)i.n.f.t.301422
    Norepinephrine (+)t1500–5450182–2630
    Salsolinol (+)440130139
    Serotonin (+)197 (>20,000)80, 290900 (1000)(29a)(18a)
    Stachydrine (+/−)270
    Thiamine (+)780 (434)60, 750t3.5a,b, 313.9a,b, 23
    Trimethylamine-N-oxide (+/−)33,9007370, 74,000n.t.d.
    Tyramine (+)t (107)t(87a)(138a)
    Quercetin (0)t

    • i.n.f.t., inhibition, not tested for transport; n.i.d., no inhibition detected; n.t.d., no transport detected; t, transported.

    • ↵a Uptake measurements performed in presence of an outwardly directed proton gradient.

    • ↵b Determination of the low apparent Km values is supposed to be due to the fact that only thiamine concentrations up to 100 µM were tested and the Km of an apparent high-affinity transport site was obtained.

  • TABLE 3

    Toxins that are substrates of human organic cation transporters

    Charge of major microspecies at pH 7.4 was calculated with program MarvinSketch of ChemAxon; IC50 values are presented in brackets. Aflatoxin: Tachampa et al., 2008, ethidium: Lee et al., 2009, monocrotaline: Tu et al., 2013, paraquat: Chen et al., 2007, 2009b; Astorga et al., 2012.

    Compound (Charge of Major Microspecies at pH 7.4) FunctionApparent Km (IC50) [µM]
    hOCT1hOCT2hOCT3hMATE1hMATE2-K
    Aflatoxin (0) mycotoxint (64)t (121)
    Ethidium (+) mutagenic0.81.72
    Monocrotaline (+) pneumotoxic25 (5.5)
    Paraquat (++) toxic herbicidet114n.t.d.169a, 212a (51a)(16a)

    • n.t.d. no transport detected; t, transported.

    • ↵a Uptake measurements performed in presence of an outwardly directed proton gradient.

  • TABLE 4

    Drugs, prodrugs, and drug metabolites that are transported by human organic cation transporters

    Drug metabolites are indicated in italics. Charge of major microspecies at pH 7.4 was calculated with program MarvinSketch of ChemAxon. Acyclovir: Takeda et al., 2002; Tanihara et al., 2007, albuterol: Hendrickx et al., 2013, amantadine: Busch et al., 1998; Bednarczyk et al., 2003; Amphoux et al., 2006; Tsuda et al., 2009b; Astorga et al., 2012; Sandoval et al., 2018, amiloride: Biermann et al., 2006; Ahlin et al., 2008; Choi et al., 2011; Astorga et al., 2012; Hendrickx et al., 2013, amiodarone: Hendrickx et al., 2013, amisulpride: dos Santos Pereira et al., 2014, D-amphetamine: Amphoux et al., 2006; Zhu et al., 2010; Wagner et al., 2017, apomorphine: Ahlin et al., 2008; Hendrickx et al., 2013, atecegatran: Matsson et al., 2013, atenolol: Hendrickx et al., 2013, atropine: Müller et al., 2005; Ahlin et al., 2008; Astorga et al., 2012; Chen et al., 2017b; Sandoval et al., 2018, benzamil: Hendrickx et al., 2013; berberine, Nies et al., 2008; Sun et al., 2014, buformin: Futatsugi et al., 2016, bupropion: Sandoval et al., 2018, butylscopolamine: Chen et al., 2017b, camostat: Hendrickx et al., 2013; Wittwer et al., 2013, captopril: Masuda et al., 2006, CDPCP: Lovejoy et al., 2008, cephradine: Tanihara et al., 2007, cephalexin: Tanihara et al., 2007, chloroquine: Zolk et al., 2009a; Müller et al., 2011; Belzer et al., 2013; Hubeny et al., 2016; Chen et al., 2017b, chlorprothixene: Hendrickx et al., 2013, cimetidine: Zhang et al., 1998; Ohashi et al., 1999; Ciarimboli et al., 2004; Peltekova et al., 2004; Suhre et al., 2005; Tahara et al., 2005; Masuda et al., 2006; Tanihara et al., 2007; Lee et al., 2009; Ohta et al., 2009; Tsuda et al., 2009b; Kido et al., 2011; Belzer et al., 2013; Hendrickx et al., 2013; Sprowl et al., 2013; Thévenod et al., 2013; Lechner et al., 2016; Martínez-Guerrero et al., 2016; Yin et al., 2016; Müller et al., 2018; Sandoval et al., 2018, cisplatin: Ciarimboli et al., 2005b; Yonezawa et al., 2006; Filipski et al., 2008; Sprowl et al., 2013, clidinium: Hendrickx et al., 2013, clofarabine: Drenberg et al., 2017, cobicistat: Lepist et al., 2014; Kikuchi et al., 2019, colistin: Visentin et al., 2017a, cycloguanil: van der Velden et al., 2017; Matthaei et al., 2019, cytarabine: Drenberg et al., 2017, diltiazem: Ahlin et al., 2008; Umehara et al., 2008; Tsuda et al., 2009b; Grube et al., 2011; Hendrickx et al., 2013, diphenylhydramine: Müller et al., 2005; Tsuda et al., 2009b; Zolk et al., 2009a; Belzer et al., 2013; Boxberger et al., 2014, 2018, disopyramide: Zhang et al., 1998; Hasannejad et al., 2004; Ahlin et al., 2008; Tsuda et al., 2009b; Zolk et al., 2009b; Kido et al., 2011; Belzer et al., 2013; Hendrickx et al., 2013, emtricitabine: Minuesa et al., 2009; Reznicek et al., 2017; Zeng et al., 2019, entecavir: Yang et al., 2016; Ma et al., 2017, ethambutol: Parvez et al., 2018, etilefrine: Müller et al., 2005, etoposide: Hu et al., 2012, famotidine: Bourdet et al., 2005; Sata et al., 2005; Tahara et al., 2005; Tsuda et al., 2009b; Astorga et al., 2012; Wittwer et al., 2013; Lechner et al., 2016; Martínez-Guerrero et al., 2016, fampridine: Xiao et al., 2018, fenoterol: Hendrickx et al., 2013; Tzvetkov et al., 2018, fexofenadine: Matsushima et al., 2009, fludarabine: Drenberg et al., 2017, fluorouracil: Drenberg et al., 2017, fluoxetine: Tzvetkov et al., 2013; Boxberger et al., 2014, 2018; Sandoval et al., 2018; Zhu et al., 2018, formoterol: Hendrickx et al., 2013; Tzvetkov et al., 2018, furamidine, Ming et al., 2009, gabapentin: Urban et al., 2008; Futatsugi et al., 2016, ganciclovir: Takeda et al., 2002; Tanihara et al., 2007, gentamicin: Gai et al., 2016, gemcitabine: Drenberg et al., 2017, glycopyrrolate: Hendrickx et al., 2013, ifosfamid: Ciarimboli et al., 2011, homatropine: Chen et al., 2017b, imatinib: Tanihara et al., 2009; Kido et al., 2011; Minematsu and Giacomini, 2011; Schmidt-Lauber et al., 2012; Wittwer et al., 2013; Boxberger et al., 2014; Nies et al., 2014; Blanc Mettral et al., 2019, indacaterol: Hendrickx et al., 2013; ipratropium: Zolk et al., 2009b; Nakamura et al., 2010a; Kido et al., 2011; Belzer et al., 2013; Hendrickx et al., 2013; Chen et al., 2017b, ketamine: Hendrickx et al., 2013; Keiser et al., 2018, lamivudine: Jung et al., 2008; Minuesa et al., 2009; Chen et al., 2017b, lappaconitine: Hendrickx et al., 2013, levofloxacin: Okuda et al., 2006; Tanihara et al., 2007, lidocaine: Hasannejad et al., 2004; Peltekova et al., 2004; Umehara et al., 2008, memantine: Busch et al., 1998; Amphoux et al., 2006; Ahlin et al., 2008; Hendrickx et al., 2013, mepenzolate: Hendrickx et al., 2013, metformin: Bourdet et al., 2005; Kimura et al., 2005, 2009; Masuda et al., 2006; Tanihara et al., 2007; Chen et al., 2009b, 2010a, 2017b; Nies et al., 2009; Zolk et al., 2009a; Meyer zu Schwabedissen et al., 2010; Astorga et al., 2012; Belzer et al., 2013; Hendrickx et al., 2013; Nakamichi et al., 2013; Futatsugi et al., 2016; Lechner et al., 2016; Martínez-Guerrero et al., 2016; Sandoval et al., 2018, metamphetamine: Wagner et al., 2017, metoclopramide: Ahlin et al., 2008; Hendrickx et al., 2013; Matthaei et al., 2016, mildronate: Grube et al., 2006; Grigat et al., 2009, nadolol: Misaka et al., 2016, naratriptan: Matthaei et al., 2016, nitidine: Li et al., 2014, nizatidine: Hendrickx et al., 2013, morphine: Ahlin et al., 2008; Tzvetkov et al., 2013; Zhu et al., 2018, oxophenonium: Hendrickx et al., 2013, oxaliplatin: Yonezawa et al., 2006; Yokoo et al., 2007, 2008; Jong et al., 2011; Sprowl et al., 2013, oxytrospium: Wenge et al., 2011, pentamidine: Jung et al., 2008; Ming et al., 2009; Kido et al., 2011; Wittwer et al., 2013, perphenazine: Hendrickx et al., 2013, phenamil: Hendrickx et al., 2013, phenformin: Dresser et al., 2002; Suhre et al., 2005; Astorga et al., 2012; Hendrickx et al., 2013; Futatsugi et al., 2016, picoplatin: More et al., 2010, pindolol: Bednarczyk et al., 2003; Umehara et al., 2008; Hendrickx et al., 2013, pirbuterol: Tzvetkov et al., 2018, pivaloylcarnitine: Ohnishi et al., 2008, pramipexole: Knop et al., 2015, prazosin: Hayer-Zillgen et al., 2002; Ahlin et al., 2008, 2011; Minematsu et al., 2010; Hendrickx et al., 2013; Wittwer et al., 2013; Moss et al., 2015, procaterol: Hendrickx et al., 2013, procainamide: Gorboulev et al., 1997; Zhang et al., 1998; Wu et al., 2000; Bednarczyk et al., 2003; Hasannejad et al., 2004; Masuda et al., 2006; Tanihara et al., 2007; Umehara et al., 2008; Astorga et al., 2012; Hendrickx et al., 2013, proguanil: Astorga et al., 2012; van der Velden et al., 2017; Matthaei et al., 2019, propranolol: Dudley et al., 2000; Urakami et al., 2004; Ahlin et al., 2008; Santini et al., 2008; Umehara et al., 2008; Zolk et al., 2009a,b; Grube et al., 2011; Astorga et al., 2012; Belzer et al., 2013; Hendrickx et al., 2013; Matthaei et al., 2016, prothionamide: Parvez et al., 2018, pyrilamine: Ohashi et al., 1999, 2002; Yabuuchi et al., 1999; Grigat et al., 2007, quinine: Gorboulev et al., 1997; Müller et al., 2005; Masuda et al., 2006; Tanihara et al., 2007; Ahlin et al., 2008; Grigat et al., 2009; Astorga et al., 2012; Tzvetkov et al., 2012; Hubeny et al., 2016; van der Velden et al., 2017, quinidine: Ohashi et al., 1999, 2002; Bednarczyk et al., 2003; Hasannejad et al., 2004; Peltekova et al., 2004; Bourdet et al., 2005; Masuda et al., 2006; Grigat et al., 2007, 2009; Ahlin et al., 2008, 2011; Umehara et al., 2008; Tsuda et al., 2009b; Zolk et al., 2009a; Minematsu et al., 2010; Astorga et al., 2012; Belzer et al., 2013; Hendrickx et al., 2013; Lechner et al., 2016; Sandoval et al., 2018, ranitidine: Bednarczyk et al., 2003; Bourdet et al., 2005; Müller et al., 2005; Tahara et al., 2005; Tsuda et al., 2009b; Meyer zu Schwabedissen et al., 2010; Astorga et al., 2012; Hendrickx et al., 2013; Martínez-Guerrero et al., 2016, relebactam: Chan et al., 2019, ribavirin: Drenberg et al., 2017, rizatriptan: Matthaei et al., 2016, salbumatol: Salomon et al., 2015; Tzvetkov et al., 2018, saracatinib: Harrach et al., 2017, selegiline: Hendrickx et al., 2013, sulpiride: dos Santos Pereira et al., 2014; Bai et al., 2017a; Li et al., 2017; Takano et al., 2017, sumatriptan: Hendrickx et al., 2013; Matthaei et al., 2016, terazosine: Ahlin et al., 2008; Hendrickx et al., 2013, terbutaline: Hendrickx et al., 2013; Tzvetkov et al., 2018, tetracycline: Tanihara et al., 2007, tiotropium: Nakamura et al., 2010a; Hendrickx et al., 2013, triamterene: Hendrickx et al., 2013, tropisetron: Tzvetkov et al., 2012, 2013, topotecan: Tanihara et al., 2007; Wittwer et al., 2013; Lechner et al., 2016, trimethoprim: Urakami et al., 2004; Sata et al., 2005; Ahlin et al., 2008; Jung et al., 2008; Belzer et al., 2013; Hendrickx et al., 2013; Lepist et al., 2014; Lechner et al., 2016; Martínez-Guerrero et al., 2016; Chen et al., 2017a; Sandoval et al., 2018; Kito et al., 2019, trospium: Choi et al., 2011; Wenge et al., 2011; Bexten et al., 2015; Hacker et al., 2015; Chen et al., 2017b, valproylcarnitine: Ohnishi et al., 2008, varenicline: Feng et al., 2008; Hendrickx et al., 2013, verapamil: Zhang et al., 1998; Yabuuchi et al., 1999; Wagner et al., 2000; Ohashi et al., 2002; Peltekova et al., 2004; Grube et al., 2006, 2011; Grigat et al., 2007, 2009; Ahlin et al., 2008, 2011; Tsuda et al., 2009b; Zolk et al., 2009b; Minematsu et al., 2010; Astorga et al., 2012; Belzer et al., 2013; Hendrickx et al., 2013; Tzvetkov et al., 2013; Boxberger et al., 2014; Jouan et al., 2014; Bexten et al., 2015; Parvez et al., 2018; Sandoval et al., 2018; Zhu et al., 2018, xamoterol: Hendrickx et al., 2013, zolmitriptan: Matthaei et al., 2016.

    Drug (Charge of Major Microspecies at pH 7.4) Medical ApplicationApparent Km (IC50) [µM]
    hOCT1hOCT2hOCT3hOCTN1hOCTN2hMATE1hMATE2-K
    Acyclovir (0) antiviral1512640a4320a
    Albuterol (+) antiasthmatictt
    Amantadine (+) antiviral(10, 236)10–51 (23)(>1000)(7.5,a 112a)(89,a 1170a)
    Amiloride (+) diuretict (57)95 (23)(2.4a)t (3.1a)
    Amiodarone (+) antiarrhythmicn.t.d. (21)t
    Amisulpride (+) antischizophrenic31168192180185
    D-Amphetamine (+) stimulantn.t.d. (97, 202)0.8, 534 (0.7–145)n.t.d. (24–460)14a (94a)16a (158a)
    Apomophine (+) anti-Parkinsonn.t.d.t
    Atecegatran, (+), anticoagulanttt
    Atenolol (+) antihypertensivett
    Atropine (+) mydriatic5.9 (1.2–12)4.4 (1.3–38)48 (42, 446)(5.9a)(53a)n.t.d. (5.9,a 18a)n.t.d. (53,a 69a)
    Benzamil (+) diuretictt
    Berberin (+) antidepressant151.0, 4.4 (0.4–0.9)2.2 (0.4–10)
    Buformin (+) antidiabetict
    Bupropion (+) antidepressantn.t.d.t (8.6–32)
    Butylscopolamine (+) spasmolytic23 (28)16 (1820)110 (2572)29a (8.2a)n.t.d. (38a)
    Camostat (+) antineoplastic,tn.t.d. (17)(2.9a)(13a)
    Captopril (−) antihypertensivet
    cDPCP (+) antineoplastictt
    Cephradine (+−) antibiotictn.t.d.
    Cephalexin (+) antibiotictn.t.d.
    Cephaloridine (+) antibiotic(<1000)t (790)
    Chloroquine (++) antimalarial(13, 1097)(8.9–1096)t (1.5a)(4.0a)
    Chlorprothixene (+) antipsychioticn.t.d.t
    Cimetidine (0) antacid60 (95–2830)15, 73 (1–560)(88, 240)(435)(<1000)2.2,a 170a (1.1a–37,a 6.7)120,a 370a (5.5a–47,a 39)
    Clidinium (+) anti ulcert
    Cisplatin (++−) antineoplastict11 (1.5)n.t.d.n.t.d.n.t.d.tt
    Clofarabine (0) antineoplastict
    Cobicistat (0) antiviralt (24)(>100)(1.9,a 4.4a)(3.2,a 36a)
    Colistin (++++) antibioticn.t.d.n.t.d.t (22.7, 2500)
    Cycloguanil (+), antimalarialt (18)tttt
    Cytarabine (0) antineoplasticn.t.d.n.t.d.n.t.d.2.0n.t.d.
    O-desmethyltramadol (+) analgetic149 (172)
    Diltiazem (+) antihypertensivet (1.7–16)n.t.d., (>1000)(50)(126)(13a)(117a)
    Diphenylhydramine (+) antiemetict (3.4, 4.1)(5.8–21)(87a)(267a)
    Disopyramide (+) antiarrhythmict (15, 82)n.t.d., (2.9–324)t (457)(84,a 66)(292a)
    Emtricitabine (0) antiviral(0.00002)(0.002)n.t.d. (0.0005)490, 13,300n.t.d.tn.t.d.
    Entecavir (0) antiviral300t24001900200,a 1600a200,a 900a
    Etoposide (0) antineoplastic150 (55)
    Ethambutol (+) antibiotic526212337455
    Etilefrine (+) hypertensive(447)(4009)2800 (4450)
    Famotidine (0) antacidt (28, >300)56 (36, 114)(6.7, 11)(0.3a–6.7a)(3.1a–36a)
    Fampridine (+) treatment of MS51 (67)n.t.d., n.i.d.n.t.d., n i.d.
    Fenoterol (+) antiasthmatic1.8t20
    Fexofenadine (+−) antiallergictn.t.d.
    Fludarabine (−) antineoplastict
    Fluorouracil (−) antineoplastict
    Formoterol (+) antiasthmatictn.t.d.
    Fluoxetine (+) antidepressantt (6.0–9.1)(3.3–57)
    Furamidine (+) antiparasitic6.1 (7.4)t (182)n.d.t. (20)
    Gabapentin (+−) antiepileptic417
    Ganciclovir (0) antiviral5165120a4280a
    Gentamicin (+++++) antibiotict
    Gemcitabine (0) antineoplastict (38,000)
    Glycopyrrolate (+) antisecretorytt
    Homatropine (+) mydriaticn.t.d. (4.0)1.3 (45)140 (13)n.t.d. (19a)n.t.d. (128a)
    Ifosfamid (0) antineoplastict (624)
    Imatinib (+) antineoplasticn.t.d. (0.1–107)n.t.d. (<1–6.7)n.t.d. (4.4, 26)t (31)n.t.d.t (0.02a–0.35a)(0.5a–2.9a)
    Indacaterol (+) brochodilatatortn.t.d.
    Ipratropium (+) bronchodilatator9, 14 (0.2–17)0.3 (0.17–15)1.7 (2.5)444 (>1000)53 (>1000)45a (31a)96a (63a)
    Ketamine (+) analgetic74a34a53,a 365n.t.d.n.t.d.
    Lamivudine (0) antiviral249, 1250 (1 × 10−5, 1900)249, 1900 (8 × 10−6, 3450)2140 (2 × 10−5, 2400)(>1000a)(1510a)
    Lappaconitine (+) analgesicn.t.d.t
    Levofloxacin (−) antibiotic(127)t
    Lidocaine (+) antiarrhythmic(294)139 (656)(0.8)
    Mepenzolate (+) anti GI ulcerst
    Metamphetamine (+) stimulantn.t.d. (0.3, 400)2.1 (1.2, 58)n.t.d. (300)21a (107a)18a (84a)
    Metformin (++), antidiabetic1470, 2160 (1230, 9480)285–3170 (521–2370)1090, 2260 (2330)t227a–780,a (47a–667a)1050,a 1980a (89a–6516a)
    Metoclopramide (+) antiemetict (16, 95)t
    Memantine (+) anti-Parkinsonn.t.d. (4, 27)34 (7.3)(236)
    Mildronate (+−) cardioprotective26 (21)
    Morphine (+) pain relieving3.4 (4.2, 28)tn.t.d. (538)n.t.d.
    Nadolol (+), antihypertensivet122531a372a
    Naratriptan (+) antimigrainet (25)
    Nitidine (+) antimalarialttt
    Oxaliplatin (++−) antineoplastict>1000tt (950)t (8900)tt
    Oxophenonium (+) antiulcertt
    Oxibutynin (+) antioveractive bladder8.8 (20)t (128)t (130)
    Pentamidine (++) antiparasitic36 (16, 22)t (1.2–11)n.t.d, (<1–15)(2.0, 2.7a)10 (10a)
    Perphenazine (+) antidepressanttn.t.d.
    Phenamil (0) stimulantn.t.d.t
    Phenformin (+) antidiabetict (10)t (15, 65)t(6.1a)(11a)
    Pirbuterol (+) antiasthmatict
    Picoplatin (+++−) antineoplasticttt
    Pindolol (+) antihypertensiven.t.d., (10, 39)t(>1000)
    Pivaloylcarnitine (+−) anti-inflammatory166 (308)
    Prazosin (+) antihypertensiven.t.d. (1.6–51)t (14, 80)(14)(1.6a)
    Pramipexole (+) anti-Parkinsontt
    Procaterol (+) antiasthmatictt
    Procainamide (+) antiarrhythmict (15, 74)t (28, 406)t (355, 738)1230,a (24,a 217a)1580,a 4100a (19,a 178a)
    Proguanil (+) prodrug, antimalarial8.1, 189.1tt (4.4a)n.t.d. (1.4a)
    Propanolol (+) antiarrhythmicn.t.d. (1.3–113)12 (67–229)(78, 113)(7.8a)(7.7a)
    Prothionamide (0) antituberculosis806
    Pyrilamine (+) antiallergict (182)t (<500)
    Quinine (+) antimalarialn.t.d. (3.5–96)n.t.d. (3.4–23)(37)t (1.9a)t (6.4a)
    Quinidine (+) antiarrhythmicn.t.d. (5–340)n.t.d. (6.4–91)216 (18)t (68)t (<500)(1.6a –>100a)n.t.d, (1.5a–29a)
    Ranitidine (++) antacid63, 70 (22–33)65 (76)n.t.d. (290, 372)(5.4a–25,a 18, 19)(10,a 25a)
    Relebactam (+−) in combination with β-lactam antibioticstt
    Ribavirin (0) antiviralt
    Rizatriptan (+) antimigrainet (41)
    Salbumatol (+) antiasthmatict
    Saracatinib (+) antirheumatict (57)t (0.9)t (50)42 (0.072)n.t.d.n.d.t.
    Selegiline (+) anti-Parkinsonn.t.d.t
    Sumatriptan (+) antimigraine55 (47)t
    Sulpiride (+) antidepressant2.6, 260 (182)26–18716025023515,a 4026,a 60
    Terazosine (+) treatment of micturition disturbancet (24)t
    Terbutaline (+) antiasthmatictt
    Tetracycline (−) antibiotict
    Trimethoprim (+) antibiotict (20–57)t (14–1318)(12)2.3 (2.7a–>100a)0.018 (0.42a–1.9a)
    Tiotropium (+) bronchodilatatortttt
    Topotecan (+) antineoplastic(61)70a (1.3a–27a)60a (5.4a–16,a 8.6)
    Triamterene (0) diuretictt
    Tropisetron (+) antiemetict (3.3, 8.5)
    Trospium (+) treatment of overactive bladder15–106 (5.3–18)0.6, 8.0 (0.07–7.3)4.4 (12–1000)(>100)15a (12a)8.2a (5.1a)
    Valproylcarnitine (+−) anti-inflammatory168 (458)
    Varenicline (+) antismoke addictiont370
    Verapamil (+) antiarrhythmicn.t.d. (1–33)n.t.d. (0.6–92)(57)t (8–25)t (21, 51)(28,a 42a)t (32,a 38a)
    Xamoterol (+) cardiac stimulanttt
    Zolmitriptan (+) antimigrainet (>1000)

    • n.t.d., no transport detected under the employed experimental conditions; t, transported.

    • ↵a Uptake measurements performed in presence of an outwardly directed proton gradient; IC50 values are presented in brackets.

  • TABLE 5

    Modeling of tertiary structures of OCTs and hMATE2-K

    The analysis of homology was performed with program EMBOSS Needle (EMBL-EBI).

    Transporter (Modeled Conformation)Crystallized Model Transporter (Conformational)Homology a.a. Identity (a.a. Similarity)ProcedureReferences
    rOCT1 (i-open)Lactose permease LacY from E. coli (i-open)14.8% (23.0%)Crystal structure–based homology modelingAbramson et al., 2003; Popp et al., 2005
    rOCT1 (o-open)Based on prediction of structural changes of modeled i-open stateVolk et al., 2009
    hOCT1 (i-open)Glycerol-3-phosphate transporter GlpT from E. coli (i-open)15.0% (25.5%)Crystal structure–based homology modelingHuang et al., 2003; Boxberger et al., 2018
    hOCT1 (o-open)Several members of the MFSIntegrative combinational modelingRoy et al., 2010; Dakal et al., 2017
    rOCT2 (i-open)LacY from E. coli (i-open)14.0% (24.0%)Crystal structure–based homology modelingAbramson et al., 2003; Schmitt et al., 2009
    rabbit OCT2 (i-open)Lactose permease LacY and glycerol-3-phosphate transporter GlpT from E. coli (i-open)14.4% (22.3%) 10.5% (20.0%)Crystal structure–based homology modelingAbramson et al., 2003; Huang et al., 2003; Zhang et al., 2005
    hOCT2 (i-open)Lactose permease LacY and glycerol-3-phosphate transporter GlpT from E. coli (i-open)13.4% (23.2%) 14.6% (26.2%)Crystal structure–based homology modelingAbramson et al., 2003; Huang et al., 2003; Pelis et al., 2006
    hOCT3 (i-open)Glycerol-3-phosphate transporter GlpT from E. coli (i-open)15.3% (26.4%)Crystal structure–based homology modelingHuang et al., 2003; Chen et al., 2010a
    mOCT3 (o-open)Human glucose transporter GLUT3 (o-occ)19.5% (34.2%)Crystal structure–based homology modelingDeng et al., 2015; Song et al., 2019
    hMATE2-K (o-open)MATE transporter NorM from vibrio cholerae (o-open)17.6% (34.4%)Crystal structure–based homology modelingHe et al., 2010; Choi et al., 2011

    • a.a, amino acid; i-open, inward open conformation; o-occ, outward occluded conformation; o-open, outward open conformation.

  • TABLE 6

    Abundance of mRNA and protein of human organic cation transporters in various organs, tissues, and cells

    The degree of expression of mRNA (crosses) is estimated from observations reported in the literature. The related references are indicated in normal face. Due to partially differing results, only an arbitrary classification could be performed. Detection of protein by Western blotting, immunohistochemistry, or proteomics is indicated by asterisks. The related references are indicated in italics when only protein expression was investigated and in underlined normal face when both mRNA and protein were not determined. The clasification has been performed on the basis of the following publications: hOCT1: Gorboulev et al., 1997; Pietig et al., 2001; Alcorn et al., 2002; Motohashi et al., 2002; Bottalico et al., 2004, 2007; Lips et al., 2005, 2007; Nishimura and Naito, 2005; Ballestero et al., 2006; Hilgendorf et al., 2007; Meier et al., 2007; Minuesa et al., 2008; Okabe et al., 2008; Zhang et al., 2008; Nies et al., 2009; Tzvetkov et al., 2009; Moreno-Navarrete et al., 2011; Gupta et al., 2012; Geier et al., 2013; Han et al., 2013; Drozdzik et al., 2014, 2019; Bexten et al., 2015; Cai et al., 2016; Arner et al., 2018; Breining et al., 2018, skin: K. Lips and H. Koepsell, unpublished data, hOCT2: Gorboulev et al., 1997; Busch et al., 1998; Pietig et al., 2001; Alcorn et al., 2002; Motohashi et al., 2002; Bottalico et al., 2004, 2007; Lips et al., 2005, 2007; Nishimura and Naito, 2005; Hilgendorf et al., 2007; Minuesa et al., 2008; Okabe et al., 2008; Filipski et al., 2009; Moreno-Navarrete et al., 2011; Bschleipfer et al., 2012; Geier et al., 2013; Sprowl et al., 2013; Bexten et al., 2015; Cai et al., 2016; Arner et al., 2018; Breining et al., 2018; Dolberg and Reichl, 2018, skin: K. Lips and H. Koepsell, unpublished data, hOCT3: Wu et al., 2000; Motohashi et al., 2002; Bottalico et al., 2004, 2007; Lips et al., 2005, 2007; Müller et al., 2005; Nishimura and Naito, 2005; Sata et al., 2005; Hilgendorf et al., 2007; Minuesa et al., 2008; Okabe et al., 2008; Nies et al., 2009; Duang and Wang, 2010; Solbach et al., 2011; Bschleipfer et al., 2012; Geier et al., 2013; Lee et al., 2014a; Bexten et al., 2015; Cai et al., 2016; Arner et al., 2018; Breining et al., 2018; Drozdzik et al., 2019; Song et al., 2019, skin: K. Lips and H. Koepsell, unpublished data, hOCTN1: Tamai et al., 1997; Pietig et al., 2001; Alcorn et al., 2002; Motohashi et al., 2002; Tokuhiro et al., 2003; Xuan et al., 2003; Kobayashi et al., 2004; Peltekova et al., 2004; Gründemann et al., 2005; Nishimura and Naito, 2005; Hiasa et al., 2006; Bottalico et al., 2007; Hilgendorf et al., 2007; Horvath et al., 2007; Meier et al., 2007; Minuesa et al., 2008; Okabe et al., 2008; Grigat et al., 2009; Markova et al., 2009; McBride et al., 2009; Sugiura et al., 2010; Bexten et al., 2015; Visentin et al., 2017b; Arner et al., 2018; Berg et al., 2018; Dolberg and Reichl, 2018, hOCTN2: Tamai et al., 1998; Wu et al., 1998b; Pietig et al., 2001; Motohashi et al., 2002; Tokuhiro et al., 2003; Xuan et al., 2003; Peltekova et al., 2004; Nishimura and Naito, 2005; Grube et al., 2006; Hilgendorf et al., 2007; Horvath et al., 2007; Meier et al., 2007; Minuesa et al., 2008; Okabe et al., 2008; Grigat et al., 2009; Geier et al., 2013; Bexten et al., 2015; Mooij et al., 2016; Berg et al., 2018; Dolberg and Reichl, 2018, hMATE1: Otsuka et al., 2005; Masuda et al., 2006; Tanihara et al., 2007; Ahmadimoghaddam et al., 2013; Geier et al., 2013; Motohashi et al., 2013; Bexten et al., 2015; Cai et al., 2016; Nies et al., 2016; Arner et al., 2018; Berg et al., 2018; Breining et al., 2018; Drozdzik et al., 2019, hMATE2-K: Masuda et al., 2006; Tanihara et al., 2007; Geier et al., 2013; Motohashi et al., 2013; Cai et al., 2016; Arner et al., 2018.

    Organ, Issue, or CellshOCT1hOCT2hOCT3hOCTN1hOCTN2hMATE1hMATE2-K
    Adipose tissue+n.d.++*+++,*n.d.
    Adrenal gland+n.d.++++++++,*(+)
    Bladder (urothelium)+,*++,*+++
    Bone marrow+n.d.++++++(+)(+)
    Brain+++(+)+++
    Brain microvessels++++++,*n.d.++++,*++
    Colon+,*n.d.+,*++++n.d.(+)
    Dorsal root ganglia+
    Erythrocyte progenitor cells+
    Eye, cornea+n.d.+++
    Eye, iris/ciliary body+++++
    Eye, retina/choriodea+++n.d.(+)++
    Fibroblasts+
    Granulocytes+
    Heart+n.d.+++++, *+(+).
    Kidney++,*+++,*+++++++,*+++,*
    Liver++++, *n.d.++, *++,*++, *(+)
    Lung+,*+,*++,*+,*+,*+(+)
    Lymphocytes+,*+,*+,*+,**
    Macrophages+,*+,**
    Mammary gland+++++++++
    Monocytes+n.d.+,*+,*+
    Nasal mucosa+,*+,*+,*
    Ovaryn.d.(+)+++(+)
    Pancreas+n.d.+(+)+
    Placenta++++,*++++(+)
    Prostate++++++++,*(+)
    Salivary glands+n.d.+++,*+++(+)(+)
    Skeletal muscle+n.d.+++++++++++
    Skin+,*+,*+,*+,*+
    Small intestine+, *n.d.+, *++++n.d.(+)
    Sperm cells**
    Spinal cord(+)+++++
    Spleen++++++(+).
    Stomach+(+)++++n.d.n.d.
    Testis+++++++++
    Thymus(+)n.d.+++—(+)
    Thyroid gland+n.d.+++++
    Trachea+,*+,*++,*++,*+,*+,*
    Uterus+(+)++,*+++(+)

    • ++++, very high expression; +++, high expression; ++, expression; +, low but significant expression; (+), low border-significant expression; n.d., no expression of mRNA detected.

  • TABLE 7

    Expression of human organic cation transporters in tumors in different organs detected on mRNA and/or protein level

    hOCT1: Kantarjian et al., 2004; Ballestero et al., 2006; Zhang et al., 2006; Monks et al., 2007; Wang et al., 2008; Schaeffeler et al., 2011; Heise et al., 2012; Herraez et al., 2013; Lin et al., 2013; Cai et al., 2016; Visentin et al., 2017b; Al-Abdulla et al., 2019, hOCT2: Rhodes et al., 2004; Zhang et al., 2006; Monks et al., 2007; Filipski et al., 2009; Burger et al., 2010; Lin et al., 2013; Cai et al., 2016; Liu et al., 2016b; Visentin et al., 2018, hOCT3: Rhodes et al., 2004; True et al., 2006; Monks et al., 2007; Tomlins et al., 2007; Wang et al., 2007; Eeles et al., 2008; Yokoo et al., 2008; Cui et al., 2011; Schaeffeler et al., 2011; Heise et al., 2012; Lin et al., 2013; Cai et al., 2016; Hu et al., 2018, hOCTN1: Rhodes et al., 2004; Monks et al., 2007; Wang et al., 2007; Drenberg et al., 2017; Visentin et al., 2017b; Hu et al., 2018, hOCTN2: Rhodes et al., 2004; Monks et al., 2007; Wang et al., 2007; Fink et al., 2019, MATE1: Cai et al., 2016, hMATE2-K: Cai et al., 2016; Liu et al., 2016b.

    Cancerous Tissue, LocalizationhOCT1hOCT2hOCT3hOCTN1hOCTN2MATE1hMATE2-K
    Breast cancer++++, d+++
    Buccal squamosal cell carcinoma+, i
    Colon cancer+, s+, i+, i
    Cholangiocarcinoma+, d
    Glioblastoma+, i
    Hepatocellular carcinoma+, d+, s, d+, i
    Lung non-small cell carcinoma+, s+, d+, s, d+, s, d+, s
    Myeloic leukemia++
    Esophageal cancer+, s+, s+, s
    Ovary cancer(+)+, d
    Prostate cancer(+)+, d
    Rectal cancer+, i
    Renal cell carcinoma+, d+, s+, d++, d
    Stomach cancer+, i
    Uterin cancer+, d

    • +, expression; (+), probable expression; d, decreased expression in tumor versus respective organ; i, increased expression in tumor versus respective organ; s, similar expression in tumor and respective organ.

  • TABLE 8

    Nonsynonymous genetic variants of human organic cation transporters with analyzed impact on function and/or expression

    MAFs reported from different groups are presented in the order of their appearance in the literature. Superscript letters indicate the numbers of employed individuals in the studies: a, 200; b, 60; c, 20; d, 455; e, 570; f, 220; g, 116; h, 240; i, 3023; k, 125; l, 150; m, 96; n, 7968; o, 160; p, 120; q, 100; r, 623; s, 89; t, 136; u, 68. References in which the indicated MAFs are reported are printed in italics. SLC22A1: Ser14Phe: Shu et al., 2003; More et al., 2010; Seitz et al., 2015, Ser29Leu: Seitz et al., 2015, Phe41Leu: Itoda et al., 2004, Arg61Cys: Kerb et al., 2002; Shu et al., 2003; Chen et al., 2010b, 2017b; More et al., 2010; Saadatmand et al., 2012; Tzvetkov et al., 2012, 2013, 2018; dos Santos Pereira et al., 2014; Dujic et al., 2015; Seitz et al., 2015; Matthaei et al., 2016, 2019, Leu85Phe: Shu et al., 2003, Leu85Phe: Shu et al., 2003, Cys88Arg: Kerb et al., 2002; Saadatmand et al., 2012; Dujic et al., 2015; Seitz et al., 2015, Gln97Lys: Chen et al., 2010b, Pro117Leu: Itoda et al., 2004; Seitz et al., 2015, Phe160Leu: Kerb et al., 2002; Shu et al., 2003; Itoda et al., 2004; Sakata et al., 2004; Kang et al., 2007; Chen et al., 2010b, Ser189Leu: Shu et al., 2003; More et al., 2010; Seitz et al., 2015, Pro197Ser: Herraez et al., 2013; Seitz et al., 2015, Arg206Cys: Yoon et al., 2013; Seitz et al., 2015, Gly220Val: Shu et al., 2003; Chen et al., 2010b; More et al., 2010; Seitz et al., 2015, Thr245Met: Seitz et al., 2015, Pro283Leu: Sakata et al., 2004; Kang et al., 2007, Glu284Lys: Seitz et al., 2015, Arg287Gly: Sakata et al., 2004, Pro341Leu: Shu et al., 2003; Itoda et al., 2004; Kang et al., 2007; Chen et al., 2010b; More et al., 2010; Yoon et al., 2013, Arg342His: Shu et al., 2003; Gly401Ser: Kerb et al., 2002; Shu et al., 2003; Chen et al., 2010b, 2017b; More et al., 2010; Saadatmand et al., 2012; Tzvetkov et al., 2012, 2018; dos Santos Pereira et al., 2014; Dujic et al., 2015; Seitz et al., 2015; Matthaei et al., 2019, Met408Val: Kerb et al., 2002; Shu et al., 2003; Itoda et al., 2004; Kang et al., 2007; Chen et al., 2010b; More et al., 2010, Gly414Ala: Kerb et al., 2002, Met420del: Kerb et al., 2002; Shu et al., 2003, 2007; More et al., 2010; Saadatmand et al., 2012; Tzvetkov et al., 2012, 2013, 2018; dos Santos Pereira et al., 2014; Dujic et al., 2015; Seitz et al., 2015; Chen et al., 2017b; Liang et al., 2018; Matthaei et al., 2019, Met440Ile: Shu et al., 2003, Ile449Thr: Seitz et al., 2015, Val461Ile: Shu et al., 2003, Gly465Arg: Kerb et al., 2002; Shu et al., 2003; Chen et al., 2010b; More et al., 2010; Saadatmand et al., 2012; Dujic et al., 2015; Arg488Met: Shu et al., 2003. SLC22A2: Pro54Ser: Leabman et al., 2002, Pro160Ser: Leabman et al., 2002, Phe161Leu: Leabman et al., 2002, Met165Val: Leabman et al., 2002, Met165Ile: Leabman et al., 2002, Thr199Ile: Kang et al., 2007; Song et al., 2008a, Yoon et al., 2013, Thre201Met: Kang et al., 2007; Song et al., 2008a; Yoon et al., 2013, Ala270Ser: Leabman et al., 2002; Kang et al., 2007; Song et al., 2008a,b; Chen et al., 2009a, 2017b; Zolk et al., 2009a; Yoon et al., 2013; Teft et al., 2017, Ala297Gly: Leabman et al., 2002, Arg400Cys: Leabman et al., 2002, Lys432Gln: Leabman et al., 2002. SLC22A3: Thr44Met: Chen et al., 2010a, Ala116Ser: Chen et al., 2010a, Leu186Phe: Chen et al., 2010a, Met370Ile: Lazar et al., 2008, Val388Met: Chen et al., 2010a, Thr400Ile: Chen et al., 2010a; Yoon et al., 2013, Val423Phe: Chen et al., 2010a; Yoon et al., 2013, Ala439Val: Nies et al., 2011b, Gly475Ser: Nies et al., 2011b. SLC22A4: Val159Met: Urban et al., 2007, Asp165Gly: Urban et al., 2007, Met205Ile: Urban et al., 2007; Dujic et al., 2015, Arg282Stop: Urban et al., 2007, Ile306Thr: Urban et al., 2007; Toh et al., 2009; Yoon et al., 2013; Futatsugi et al., 2016, Gly462Glu: Kawasaki et al., 2004, Leu503Phe: Peltekova et al., 2004; Newman et al., 2005b; Taubert et al., 2005; Urban et al., 2007, 2008; Toh et al., 2009; Pochini et al., 2012; Yoon et al., 2013; Dujic et al., 2015; Futatsugi et al., 2016. SLC22A5: Phe17Leu: Urban et al., 2006, Trp132Stop: Koizumi et al., 1999; Tang et al., 1999, Leu144Phe: Urban et al., 2006, Met179Leu: Koizumi et al., 1999, Tyr211Cys: Vaz et al., 1999, Arg282Stop: Vaz et al., 1999; Wang et al., 1999, Trp283Cys: Koizumi et al., 1999, Met352Arg: Seth et al., 1999, Tyr401Stop: Wang et al., 1999, Tyr449Asp: Urban et al., 2006; Amat di San Filippo et al., 2008, Ser467Cys: Koizumi et al., 1999; Ohashi et al., 2002, Glu475Arg: Wang et al., 2000a, Pro478Leu: Seth et al., 1999; Tang et al., 1999; Urban et al., 2006, Val481Phe: Urban et al., 2006, Val481Ile: Urban et al., 2006, Phe508Leu: Urban et al., 2006, Met530Val: Urban et al., 2006, Pro549Ser: Urban et al., 2006. SLC47A1: Val10Leu: Kajiwara et al., 2009, Gly64Asp: Chen et al., 2009b; Kajiwara et al., 2009; Yoon et al., 2013, Leu125Phe: Chen et al., 2009b, Kim et al., 2013; Yoon et al., 2013, Thr159Met: Meyer zu Schwabedissen et al., 2010, Ala310Val: Kajiwara et al., 2009, Asp328Ala: Kajiwara et al., 2009; Meyer zu Schwabedissen et al., 2010, Val338Ile: Chen et al., 2009b; Meyer zu Schwabedissen et al., 2010, Asn474Ser: Kajiwara et al., 2009, Val480Met: Chen et al., 2009b, Cys497Ser: Chen et al., 2009b, Cys497Phe: Meyer zu Schwabedissen et al., 2010, Gln519His: Chen et al., 2009b. SLC47A2: Lys64Asn: Kajiwara et al., 2009; Yoon et al., 2013, Pro162Leu: Choi et al., 2011, Gly211Val: Kajiwara et al., 2009; Yoon et al., 2013, Gly393Arg: Choi et al., 2011, Thr505Ile: Choi et al., 2011, Ala525Thr: Choi et al., 2011.

    GeneAmino Acid Exchange (MAF in Different Populations)In Vitro Uptake Compared with WT [% of WT]
    Substrate: Effect on Uptake Measured Below Km, Effect onVmax, (Effect on Km)
    SLC22A1Ser14Phe (Af: 0.031a, 0.012d; Eu: 0a, 0e; As: 0b, 0.002f, Me: 0c)TEA: ∼190, ∼100; MPP: ∼190; metformin: ∼60; picoplatin: ∼70
    Ser29Leu (Af: 0d; Eu: 0e; As: 0f)TEA: 0; MPP: 0; metformin: 0; tropisetron: 0
    Phe41Leu (Ja: 0.004g)
    Arg61Cys (Af: 0a, 0.010d; Eu: 0.156h, 0.072a, 0.009e; As: 0b, 0.0166f; Me: 0.056c)TEA: ∼30; MPP: ∼30, ∼50, (∼100, 640); metformin: ∼5; 22, (103); picoplatin: ∼20; tropisetron: ∼10; debrisoquine: ∼37, (∼100); proguanil: ∼50; cycloguanil ∼80; fenoterol: ∼30; sumatriptan: 54; ipratropium: 43; amilsulpride: ∼30; sulpride: <5
    Leu85Phe (Af: 0.01a; Eu: 0a, 0.004h; As: 0b; Me: 0c)MPP: ∼100
    Cys88Arg (Af: 0.002d; Eu: 0.012h, 0.0005e, 0.004i; As: 0.0009f)TEA: ∼6; MPP: ∼2, serotonin: ∼12; debrisoquine: 0
    Gln97Lys (EA: 0.017k)TEA: ∼60; MPP: ∼60; metformin: ∼60, 88, (280)
    Phe160Leu (Af: 0.005a; Eu: 0.340h, 0.065a, 4.6; As: 0.017b; EA: 0.12k; Me: 0.05c; Ko: 13l; Ja: 0.086g)TEA: ∼100, ∼100, (∼100); MPP: ∼100, ∼100, (∼60)
    Pro117Leu (Af: 0d; Eu: 0e; As: 0.002f; Ja: 0.004g)TEA: ∼45; MPP: ∼50; metformin: ∼55, 51, (128)
    Ser189Leu (Af: 0a, 0d; Eu: 0.005a, 0e; As: 0b, 0f; Me: 0c)TEA: ∼100, ∼20; MPP: ∼100; metformin: ∼20; picoplatin: ∼60
    Pro197SerTEA: ∼100
    Arg206Cys (Af: 0d; Eu: 0e; As: 0.001f; Ko: 0m)TEA: ∼20; MPP: ∼25; metformin: ∼20, 20, (111)
    Gly220Val (Af: 0.005a, 0d; Eu: 0a, 0e; As: 0b, 0f; Me: 0c)TEA: 0; MPP: ∼7; metformin: 0, picoplatin: ∼10
    Thr245Met (Af: 0d; Eu: 0e; As: 0.002f)
    Pro283Leu (Ko: 0.02l)TEA: 0; MPP: 0;
    Glu284Lys (Af: 0d; Eu: 0e; As: 0f, 0.14)TEA: 0; MPP: 0; metformin: 0; tropisetron: 0
    Arg287GlyTEA: 0; MPP: 0;
    Pro341Leu (Af: 0.082a; Eu: 0a; As: 0.117b; EA: 0.19k; Me: 0c; Ja: 0.168g; Ko: 0.16l, 0.135m)TEA: ∼65, 56, (63); MPP: 60–100, 56, (180); metformin: ∼100; picoplatin: ∼100
    Arg342His (Af: 0.031a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100; 1–8; picoplatin: ∼100
    Gly401Ser (Af: 0.007a, 0.0009d; Eu: 0.065h, 0.011a, 0.0047e, 0.0024i; As: 0b, 0f; Me: 0c)TEA: 1–8; MPP: <2; serotonin: ∼10; metformin: ∼10; picoplatin: ∼30; tropisetron 0; debrisoquine: ∼9, (∼100); proguanil: ∼30; cycloguanil ∼60; fenoterol: ∼30; sumatriptan: 13; ipratropium: 10; amilsulpride: ∼20; sulpride: ∼30
    Met408Val (Af: 0.74a; Eu: 0.60a; As: 0.76b; EA: 0.81k; Me: 0.79c; Ko: 74l; Ja: 0.81g)MPP: ∼100; picoplatin: ∼140
    Gly414Ala (Eu: 0.004h)
    Met420del (Af: 0.029a, 0.040d; Eu: 0.263h, 0.185a, 0.027e; 0.191i; As: 0b, 0.065f; Me: 0.21c)TEA: ∼100; MPP: ∼100, ∼100, (∼100); metformin: ∼30; picoplatin: ∼61; morphine: 25, (147); tropisetron: ∼5; debrisoquine: ∼50, (∼100); proguanil: ∼70; cycloguanil ∼100; fenoterol: ∼70; sumatriptan: ∼100, 66; ipratropium: 55; thiamine: ∼60, 30, (∼150); amilsulpride: ∼30; sulpride: ∼30
    Met440Ile (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100
    Ile449Thr (Af: 0d; Eu: 0e; As: 0f)
    Val461Ile (Af: 0.001a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100
    Gly465Arg (Af: 0a, 0.002d; Eu: 0.003h, 0.04a, 0.003e, 0.0032i; As: 0b, 0.004f; Me:0c)TEA: 0; MPP: ∼7; metformin: 0; picoplatin: ∼8; debrisoquine: 0
    Arg488Met (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100; picoplatin: ∼120
    SLC22A2Pro54Ser (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼150
    Pro160Ser (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)
    Phe161Leu (Af: 0a; Eu: 0.005a; As: 0b; Me: 0c)MPP: ∼100
    Met165Val (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100
    Met165Ile (Af: 0.01a; Eu: 0a; As: 0b; Me: 0c)TEA: decrease; MPP: ∼50, (∼100)
    Thr199Ile (Ko: 0.01l, 0m)TEA: ∼30; MPP: ∼3, ∼30, 4, (372), metformin: 3, 14, (50)
    Thr201Met (Ko: 0.02l, 0.005m)TEA: ∼50, ∼30; MPP: ∼2, ∼40, 5, (509); metformin: 1, 15, (40)
    Ala270Ser (Af: 0.11a; Eu 0.157a, 0.11n; As: 0.086a; Me: 0.15a; Ko: 0.14l, 0.078m)TEA: ∼40; MPP: ∼6, ∼40, 9, 70, (∼100), (200); metformin: 150, 9, 53, 135, (∼100); propranolol: 44, (∼50); ipratropium: 121, (∼200); TMAO: ∼100
    Ala297Gly (Af: 0a; Eu: 0.005a; As: 0b; Me: 0c)MPP: ∼80
    Arg400Cys (Af: 0.015a; Eu: 0a; As: 0b; Me: 0c)TEA: decrease; MPP: ∼30, (∼100)
    Lys432Gln (Af: 0.01a; Eu: 0a; As: 0b; Me: 0.05c)MPP: (∼56)
    SLC22A3Thr44Met (Af: 0.006a; Eu: 0.006a; As: 0b; Me: 0c)Metformin: 136, (105)
    Ala116Ser (Af: 0.02a; Eu: 0a; As: 0b; Me: 0c)Metformin: 92, (94)
    Leu186PheMetformin: 97, (95)
    Met370IleNorepinephrine: 60, 280, (210)
    Val388MetMetformin: 105, (104)
    Thr400Ile (Af: 0a; Eu: 0.005a; As: 0b; Me: 0c; Ko: 0m)Metformin: 71, (350)
    Val423Phe (Ko: 0m)Metformin: 75, (271)
    Ala439Val
    Gly475Ser
    SLC22A4Val159Met (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)TEA: ∼100; betaine: ∼80
    Asp165Gly (Af: 0°; Eu: 0°; As: 0.008p; Me: 0q)TEA: <10; betaine: 0
    Met205Ile (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)TEA: ∼60; betaine: ∼60
    Arg285Stop (Af: 006°; Eu: 0°; As: 0p; Me: 0q)TEA: 0; betaine: 0
    Thr306Ile (Af: 0.27°; Eu: 0.34°, 0.41n; As: 0.64p; Me: 0.24q; CS: 0.40m; IS: 0.14m; Ko: 0.63m)TEA: ∼70; betaine: ∼110; ergothioneine: 95, (106); gabapentin: 66, (129)
    Gly462GluTEA: 0
    Leu503Phe (Af: 0.09°; Eu: 0.41°, 0.39n; As: 0p; Me: 0.23p; Ca: 0.43r; CS: 0m; IS: 0.07m; Ko: 0m)Ergothioneine: 52, 63, (34), (47); L-carnitine: 46, (238); TEA: ∼240, 133, 316, (17), (39); gabapentin: ∼50, 273, (453); acetylcholine: ∼100, ∼100; betaine: ∼30; metformin: ∼30; buformin: ∼30; phenformin: ∼30
    SLC22A5Phe17Leu (Af: 0°; Eu: 0°; As: 0.0.7p; Me: 0q)L-carnitine: ∼60, 52, (93); TEA: ∼10, 65, (206)
    Trp132StopL-carnitine: 0
    Leu144Phe (Af: 0.075°; Eu: 0°; As: 0p; Me: 0.01q)L-carnitine: ∼100, ∼100, (∼100); TEA: ∼100, ∼100, (∼100)
    Met179LeuL-carnitine: ∼70
    Tyr211CysL-carnitine: 0
    Arg282StopL-carnitine: 0
    Trp283CysL-carnitine: ∼2
    Met352ArgL-carnitine: 0; TEA: ∼10
    Tyr401StopL-carnitine: 0
    Tyr449Asp (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)L-carnitine: ∼80; TEA: ∼170
    Glu452ArgL-carnitine: ∼4, ∼6, (∼100)
    Ser467CysL-carnitine: 9.9, 150, (1660); acetyl-L-carnitine: 13; TEA: 105, 180, (122); pyrilamine: 74; quinidine: 88; verapamil: 10
    Pro478LeuL-carnitine: ∼4; TEA: ∼370
    Val481Phe (Af: 0°; Eu: 0.006°; As: 0p; Me: 0q)L-carnitine: ∼80; TEA: ∼30
    Val481Ile (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)L-carnitine: ∼100; TEA: ∼100
    Phe508Leu (Af: 0°; Eu: 0°; As: 0p; Me: 0.01q)L-carnitine: ∼10; TEA: ∼100
    Met530Val (Af: 0°; Eu: 0°; As: 0.008p; Me: 0q)L-carnitine: ∼80; TEA: ∼150
    Pro549Ser (Af: 0.10°; Eu: 0°; As: 0p; Me: 0q)L-carnitine: ∼100, ∼100, (∼100); TEA: ∼100, ∼100, (∼100)
    SLC47A1Val10Leu (Ja: 0.022s)TEA: ∼100; metformin: ∼100
    Gly64Asp (Af: 0t; Eu: 0t; As: 0.007t; Me: 0t; Ja: 0.006s; Ko: 0.005m)TEA: 0, ∼10; metformin: ∼2, ∼7; paraquat: 0; oxaliplatin: 0
    Leu125Phe (Af: 0t; Eu: 0t; As: 0.007t; Me: 0.05t; Ko: 0.005m)TEA: ∼50; metformin: ∼60, 78, (126); paraquat: ∼70, 114, (116); oxaliplatin: ∼90
    Thr159MetTEA: ∼45; metformin: ∼45
    Ala310Val (Ja: 0.0022s)TEA: ∼20, 38, (∼376); metformin: ∼40
    Asp328Ala (Ja: 0.006s)TEA: ∼20, ∼100, 27, (∼129); metformin: ∼27, ∼100
    Val338Ile (Af: 0.05t; Eu: 0t; As: 0t; Me: 0t)TEA: ∼40, ∼50; metformin: ∼50, ∼60, 89, (116); paraquat: ∼100; oxaliplatin: ∼80
    Asn474Ser (Ja: 0.006s)TEA: ∼64, 70, (∼143); metformin: ∼98
    Gly480Ala (Af: 0t; Eu: 0t; As: 0.008t; Me: 0t)TEA: 0; metformin: ∼5; paraquat: ∼5; oxaliplatin: 0
    Cys497PheTEA: ∼100; metformin: ∼80, ∼120
    Cys497Ser (Af: 0.02t; Eu: 0t; As: 0t; Me: 0t)TEA: ∼80; metformin: ∼80; paraquat: ∼120; oxaliplatin: ∼170
    Gln519His (Af: 0.08t; Eu: 0t; As: 0t; Me: 0t)TEA: ∼90; metformin: ∼80; paraquat: ∼100; oxaliplatin: ∼90
    SLC47A2Lys64Asn (Ja: 0.006s; Ko: 0m)TEA: ∼50, 37, (∼57); metformin: ∼70
    Pro162Leu (Af: 0.06u; Eu: 0u; As: 0.09u; Me: 0u)TEA: ∼20; metformin: ∼25; amiloride: ∼50; trospium: ∼15
    Gly211Val (Ja: 0.017s; Ko: 0m)TEA: ∼2; metformin: 0
    Gly393Arg (Af: 0u; Eu: 0.009u; As: 0u; Me: 0.008u)TEA: ∼25, metformin: ∼40, amiloride: ∼50, trospium: ∼35
    Thr505Ile (Af: 0.07u; Eu: 0u; As: 0u; Me: 0u)TEA: ∼80, metformin: ∼60, amiloride: ∼105, trospium: ∼115
    Ala525Thr (Af: 0.07u; Eu: 0u; As: 0u; Me: 0u)TEA: ∼80, metformin: ∼75, amiloride: ∼130, trospium: ∼90

    • Af, Africans i.e., American Africans (research group of K. Giacomini) or Africans from North Africa, Sub-Sahara and Middle East (Seitz et al., 2015); As, American Asians (research group of K. Giacomini) or Asians from Central Asia (Seitz et al., 2015); Ca, Canadians; C/J, mixed Chinese and Japanese population; CS, Chinese from Singapore; EA, Asians from East Asia; Eu, Europeans or American Europeans; IS, Indians from Singapore; Ja, Japanese; Ko, Koreans; Me, American Mexicans.

  • TABLE 9

    Drugs that have been shown to inhibit human organic cation transporters and have not been tested for transport or could not be identified as substrate (only drugs for which an IC50 value <20 µM was determined for at least one OCT are indicated)

    Charge of major microspecies at pH 7.4 was calculated with program MarvinSketch of ChemAxon. Abacavir: Minuesa et al., 2009, abemaciclib: Chappell et al., 2019, adapalene: Kido et al., 2011, alfuzosin: Chen et al., 2017a, amitriptyline: Sata et al., 2005; Ahlin et al., 2008; Zolk et al., 2009b; Belzer et al., 2013; Tzvetkov et al., 2013; Jouan et al., 2014; Hacker et al., 2015; Matthaei et al., 2016; Sandoval et al., 2018; Zhu et al., 2018, amadiaquine: van der Velden et al., 2017, D- amphetamine: Amphoux et al., 2006, amsacrine: Ahlin et al., 2008, artemisin: Hubeny et al., 2016, atomoxetine: Sandoval et al., 2018, azidothymidine: Minuesa et al., 2009, beclomethasone: Lips et al., 2005, benzethonium: Kido et al., 2011, benztropine: Sandoval et al., 2018, bithionol: Kido et al., 2011; Wittwer et al., 2013; Chen et al., 2017a, bosutinib: Johnston et al., 2014, bucindolol: Ahlin et al., 2008, 2011, budesonide: Lips et al., 2005, buflomedil: Kido et al., 2011; Hendrickx et al., 2013, buspirone: Wittwer et al., 2013, Sandoval et al., 2018, bisoprolol: Bachmakov et al., 2009, camylofine: Chen et al., 2017a, carbetapentane: Chen et al., 2017a, carvedilol: Bachmakov et al., 2009; Zolk et al., 2009b; Grube et al., 2011; Belzer et al., 2013; Yin et al., 2016; Chen et al., 2017a, clemastine: Ahlin et al., 2008, clomacran: Kido et al., 2011, chlorhexidine: Wittwer et al., 2013, cediranib: Johnston et al., 2014, chlorphenesin: Kido et al., 2011, chlorpromazine: Bednarczyk et al., 2003; Ahlin et al., 2008, 2011; Zolk et al., 2009a; Belzer et al., 2013, citalopram: Ahlin et al., 2008; Koepsell et al., unpublished data, clomipramine: Ahlin et al., 2008; Hendrickx et al., 2013, clonidine: Zhang et al., 1998; Wu et al., 2000; Müller et al., 2005; Suhre et al., 2005; Ahlin et al., 2008; Zolk et al., 2009a; Astorga et al., 2012; Belzer et al., 2013; Hendrickx et al., 2013; Tzvetkov et al., 2013; Chen et al., 2017a, closantel: Chen et al., 2017a, clotrimazole: Chen et al., 2017a, clozapine: Hendrickx et al., 2013; Wang et al., 2019, codeine: Tzvetkov et al., 2013, darunavir: Moss et al., 2015, dasatinib: Minematsu and Giacomini, 2011, des-fluoro(6)-quinolone: Okuda et al., 2006; Imamura et al., 2011; dextromethorphan: Chen et al., 2017a, dichlorophene: Chen et al., 2017a, desipramine: Gorboulev et al., 1997; Zhang et al., 1998; Wu et al., 2000; Ahlin et al., 2008, 2011; Tsuda et al., 2009b; Zolk et al., 2009b; Chen et al., 2017a, desloratadine: Zolk et al., 2009b, dicyclomine: Kido et al., 2011, dipyramidole: Kido et al., 2011, dobutamine: Chen et al., 2017a, dolutegravir: Reese et al., 2013; Lepist et al., 2014, domperidone: Wittwer et al., 2013, donepezil: Martínez-Guerrero et al., 2016; Matthaei et al., 2016, desloratadine: Zolk et al., 2009b, dihydroergotamine: Wittwer et al., 2013, doxazosin: Ahlin et al., 2011, doxepin: Zolk et al., 2009b; Belzer et al., 2013; Hacker et al., 2015; Chen et al., 2017a, eletriptan: Matthaei et al., 2016, epinastine: Wittwer et al., 2013, erlotinib: Minematsu and Giacomini, 2011; Chen et al., 2017a, esmolol: Martínez-Guerrero et al., 2016, ethinylestradiol: Wittwer et al., 2013, ethylacridinium: Belzer et al., 2013, exemestane: Kido et al., 2011, fenfluramine: Zolk et al., 2009a, flecainide: Umehara et al., 2008; Zolk et al., 2009b; Grube et al., 2011; Belzer et al., 2013, flurazepam: Zolk et al., 2009a,b, gabexate: Kido et al., 2011; Wittwer et al., 2013, gefitinib: Galetti et al., 2010; Minematsu and Giacomini, 2011, gentian violet: Kido et al., 2011, granisetron: Wittwer et al., 2013, griseofulvin: Chen et al., 2017a, guanabenz: Kido et al., 2011; Chen et al., 2017a, guanfacine: Astorga et al., 2012, imipramine: Wu et al., 2000; Ahlin et al., 2008; Tsuda et al., 2009b; Zolk et al., 2009b; Kido et al., 2011; Belzer et al., 2013; Hendrickx et al., 2013; Tzvetkov et al., 2013; Sandoval et al., 2018; Zhu et al., 2018, imiquimod: Astorga et al., 2012, indinavir: Zhang et al., 2000; Jung et al., 2008; Wittwer et al., 2013, irinotecan: Tzvetkov et al., 2013; Wittwer et al., 2013; Sandoval et al., 2018; Zhu et al., 2018, jatrorrhizine: Sun et al., 2019, ketoconazole: Ahlin et al., 2011; Astorga et al., 2012; Chen et al., 2017a, ketotifen: Martínez-Guerrero et al., 2016, lansoprazole: Nies et al., 2011a; Hacker et al., 2015, leukomycin: Wittwer et al., 2013, mebeverine: Kido et al., 2011, 3,4-methylenedioxymethamphetamine: Amphoux et al., 2006, mexiletine: Zolk et al., 2009b; Sandoval et al., 2018, mefloquine: Hubeny et al., 2016, midazolam: Zhang et al., 1998, mitoxantrone: Meyer zu Schwabedissen et al., 2010; Wittwer et al., 2013, nelfinavir: Zhang et al., 2000; Jung et al., 2008, nifekalant: Wittwer et al., 2013, nilotinib: Minematsu and Giacomini, 2011, ondansetron: Kido et al., 2011; Tzvetkov et al., 2012, 2013; Wittwer et al., 2013; Lechner et al., 2016; Zhu et al., 2018, oxaliplatin: Yonezawa et al., 2006; Yokoo et al., 2007, 2008; Ahlin et al., 2008, 2011; Jong et al., 2011; Sprowl et al., 2013, olanzapine: Kido et al., 2011, omeprazole: Nies et al., 2011a; Martínez-Guerrero et al., 2016, orphenadrine: Ahlin et al., 2008; Kido et al., 2011, pantoprazole: Nies et al., 2011a; Wittwer et al., 2013; Hacker et al., 2015, phenoxybenzamine: Hayer-Zillgen et al., 2002; Ahlin et al., 2008, phentoloamine: Astorga et al., 2012, phenyltoloxamine: Kido et al., 2011, phenytoin: Hasannejad et al., 2004, prochlorperazine: Ahlin et al., 2008; Hendrickx et al., 2013; Martínez-Guerrero et al., 2016, procyclidine: Kido et al., 2011, proguanil: Astorga et al., 2012; van der Velden et al., 2017, promazine: Ahlin et al., 2008, propafenone: Ahlin et al., 2008, 2011; Zolk et al., 2009b; Grube et al., 2011; Belzer et al., 2013; Hendrickx et al., 2013; Chen et al., 2017a, propantheline bromide: Kido et al., 2011, pyrimethamine: Matsushima et al., 2009; Tsuda et al., 2009b; Astorga et al., 2012; Hubeny et al., 2016; Lechner et al., 2016; Yin et al., 2016; Chen et al., 2017a; van der Velden et al., 2017, quetiapine: Wang et al., 2019, rabeprazole: Kido et al., 2011; Nies et al., 2011a, repaglinide: Ahlin et al., 2008; Bachmakov et al., 2008, rapamycin: Meyer zu Schwabedissen et al., 2010, rimantadine: Wittwer et al., 2013, ritonavir: Zhang et al., 2000; Jung et al., 2008; Meyer zu Schwabedissen et al., 2010; Wittwer et al., 2013; Lepist et al., 2014; Kikuchi et al., 2019, rosiglitazone: Bachmakov et al., 2008, saquinavir: Zhang et al., 2000; Jung et al., 2008, scopolamine: Hendrickx et al., 2013; Chen et al., 2017b, sitagliptin: Hacker et al., 2015, sparteine: Kido et al., 2011, spironolactone: Grube et al., 2006, 2011; Ahlin et al., 2011; Hacker et al., 2015, sulconazole: Kido et al., 2011, sunitinib: Minematsu and Giacomini, 2011; Chen et al., 2017a, tacrine: Kido et al., 2011; Astorga et al., 2012; Chen et al., 2017a; Sandoval et al., 2018; tenatoprazole: Nies et al., 2011a, tenofovir disoproxil: Minuesa et al., 2009; Shen et al., 2017, irtetrachlorosalicylanilide: Kido et al., 2011, tolterodine: Kido et al., 2011, tramadol: Astorga et al., 2012, trimipramine: Ahlin et al., 2008; Hacker et al., 2015, tripilenamine: Sandoval et al., 2018, tubocurarine: Wittwer et al., 2013, valspodar: Lechner et al., 2016, vecuronium: Wittwer et al., 2013, zafirlukast: Wittwer et al., 2013, ziprasidone: Wang et al., 2019, zolpidem: Hacker et al., 2015.

    Drug (Charge of Major Microspecies at pH 7.4) Medical ApplicationIC50 [µM]
    hOCT1hOCT2hOCT3hOCTN1hOCTN2hMATE1hMATE2-K
    Abacavir (0) antiviral7 × 10−54 × 10−55 × 10−5
    Abemaciclib (+) antineoplastic1.50.520.75
    Adapalene (−) treatment of acne<1
    Alfuzosin (+) antiprostate hyperplasia15
    Amodiaquine (+) antimalarial11
    Amsacrine (+) antineoplastic5
    Amitriptyline (+) antidepressant1.9–580.4–14>100
    Artemisin (0) antimalarial4.2
    Atomoxetine (+) treatment of ADHS3.5–20
    Atropine (+) mydriatic1.2, 121.3–294465.9a53a
    Azidothymidine (+/−) antiviral0.00020.00030.0004
    Beclomethasone (0) antiasthmatic4.4
    Benzethonium (+) antineoplastic<1
    Benztropine (+) anti-Parkinson0.3–13
    Bithionol (−) anthelmintic2.21.9, <15.2a6.6a
    Bucindolol (+) vasodilatory15, 27
    Budesonide (0) antiasthmatic7.3
    Buflomedil (+) vasodilatoryn.t.d.<1, n.t.d.
    Buspirone (+) anxiolytic8.6–691.7a46a
    Bisoprolol (+) antihypertensive2.4
    Bosutinib (0) antichronic myeloic leukemia2.1
    Camylofine (+) muscle relaxant9.1
    Carbetapentane (+) antitussive1.6
    Carvedilol (+) antihypertensive1.4, 3.42.3–637473124,a 146a79,a 131a
    Cediranib (+) antineoplastic2.5
    Chlorhexidine (++) antiseptic0.40.7a0.5a
    Chlorphenesin (0) muscle relaxant<1
    Chlorpromazine (+) antipsychotic2.6–522.6, 14
    Clozapine (+) antidepressant1.8
    Citalopram (+) antidepressant3, 1912145
    Clemastine (+) antiallergic4.9
    Clomacran (+) sedative and hypnotic<1
    Clomipramine (+) antidepressant5, 19, n.t.d.n.t.d.
    Clonidine (+) sedative0.6–23, n.t.d.2–63, n.t.d.110, 3738.1a54a
    Cloperastine (+) antitussive15
    Closantel (−) antiparasitc3
    Clotrimazole (0) antifungal12
    Clozapine (+) antipsychotic1.8, n.t.d.
    Codeine (+) antitussive, analgesic11
    Darunavir (0) antiviral16
    Dasatinib (+) antineoplastic1.12.14.50.8a0.8a
    Des-fluoro (6)-quinolone (c.n.d.) antibiotic0.9, 1.30.8a0.1a
    Dextromethorphan (+) antitussive10
    Dichlorophene (−) antifungal8.4
    Dicyclomine (+) antispasmodic<1
    Dipyramidole (0) antithrombotic812.62674
    Donepezil (+) anti-Alzheimer0.8a–1.5a
    Desipramine (+) antidepressant5–57161456a283a
    Dihydroergotamine (+) antimigraine502.8a13a
    Dobutamine (+) treatment of heart failure4.2
    Dolutegravir (0) antiviral0.07, 1.9>1004.7a>100a
    Domperidone (0) antemetic337.92.3a15a
    Doxazosin (+) antihypertensive15
    Doxepin (+) antidepressant1.5, 120.25–13
    Eletriptan (0) antimigraine6.8
    Epinastine (+) antiallergic<1, 4.31.1a30a
    Erlotinib (0) antineoplastic0.34, 165.24.23.8,a 7.9a3.5,a 6.2a
    Esmolol (+) treatment of tachycardia11a–25a
    Ethinylestradiol (0) contraceptive2.221a20a
    Ethylacridinium (+) antiseptic0.08
    Exemestane (0) treatment of breast cancer<1
    Fenfluramine (+) appetite suppressant10
    Flecainide (+) antiarrhythmic2.5, 42191, 23460176
    Flurazepam (+) anticonvulsant53, 60
    Gabexate (+) anticoagulant0.90.5a–0.70a11a
    Gefitinib (0) antineoplastic1.1245.51.8a0.19a
    Gentian violet (+) fungicidal<1
    Granisetron (+) antiemetic4.35.0a311a
    Griseofulvin (0) antimycotic7.3
    Guanabenz (+) antihypertensive4.9<1
    Guanfacine (+) antihypertensive3.5a218a
    Imipramine (+) antidepressant6–37, n.t.d.0.4–6, n.t.d.4242,a 10183a
    Imiquimod (0) immune response modifier14a19a
    Indinavir (0) antiviral37–208142, 275>5007.8a>500a
    Irinotecan (+) antineoplastic1.4–210.31–16757.9a79a
    Jatrorrhizine (+) promoting GI motility0.12, 0.820.18, 0.28
    Ketoconazole (0) antifungal2.6, 7.41.3a9.3a
    Ketotifen (+) antiallergic13a–27a
    Lansoprazole (0) antacid363.3–9.53.1
    Leukomycin (+−) antibiotic18211a125a
    Mebeverine (+) antispasmodic<1
    Mefloquine (+) antimalarial6.615
    3,4-Methylenedioxymethamphetamine (+) stimulant241.674
    Mexiletine (+) antiarrhythmic19–50
    Midazolam (0) hypnotic, anesthetic3.7
    Mitoxantrone (++) antineoplastic4473610.5a; 4.4; 5.20.83a
    Nelfinavir (+) antiviral7, 2213
    Nifekalant (++−) antiarrhythmic>30010.31466.5a2.7a
    Nilotinib (0) antineoplastic2.9>300.353.4a1.8a
    Ondansetron (+) antiemetic0.3–640.2–161.7, 170.04a–4.0a, 0.150.03a–1.7,a 6.9
    Olanzapine (+) antipsychotic<1
    Omeprazole (0) antacid166.72216–24a
    Orphenadrine (+) muscle relaxant13, >1002.565>100
    Pantoprazole (0) treatment of gastric ulcera31, >5000.56–2.823, 13743a>500a
    Phenoxybenzamine (+) antihypertensive2.7, 1556
    Phentolamine (+) vasodilatory4.6a5.3a
    Phenyltoloxamine (+) enhancer of analgetics<1
    Phenytoin (0) anticonvulsant0.75
    Prochlorperazine (+) antipsychotic50, n.t.d.n.t.d.7.9a–15a
    Procyclidine (+) anti-Parkinson<0.1
    Proguanil (+) antimalarial134.4a1.4a
    Promazine (+) antipsychotic17
    Propafenone (+) antiarrhythmic1–16, n.t.d.3.6, 25, n.t.d.68
    Propantheline (+) treatment of hyperhidrosis<1
    Pyrimethamine (+) antimalarial8.5, 141.6–230.04a–1.2a, 0.080.01a–0.83,a 0.06
    Quetiapine (0) antidepressant13
    Rabeprazole (0) antacid3.0<1, 5.73.0
    Repaglinide (0) antidiabetic1.6, 9.2
    Rapamycin (0) immune suppressive3.3, 3.5
    Rimantadine (+) antiviral4.47.3a288a
    Ritonavir (0) antiviral5–3420, 25>1001.3a–4.4a 14, 1524,a 90a
    Rosiglitazone (−) antidiabetic6.9
    Saquinavir (+) antiviral8, 37205
    Scopolamine (0) antiemetic6.7, n.t.d.541, n.t.d.218119a700a
    Sitagliptin (+) antidiabetic7.4
    Sparteine (++) anticonvulsant, antiarrhythmic<1
    Spironolactone (0) antihypertensive1.2, 31.37312526, 36
    Sulconazole (0) antifungal<1
    Sunitinib (+) antineoplastic0.33, 6.11.75.20.28a0.86
    Tacrine (+) anti-Alzheimer22, 830.4–2.30.5a, 1.11.1,a >100
    Tenatoprazole (0) antacid232015
    Tenofovir disopoxil (0) antiviral9 × 10−5, >106 × 10−55 × 10−7
    Tetrachlorosalicylanilide (−) antiseptic<1
    Tolterodine (+) spasmolyticum<1
    Tramadol (+)18a75a
    Trimipramine (+) antidepressant280.44
    Tripelenamine (+) antiallergic2.1–12
    Tubocurarine (++) muscle relaxant799.4a56a
    Valspodar (0), antidrug resistant2.0a–>15a0.11a–0.24a
    Vecuronium (++) muscle relaxant3.51.9a25a
    Zafirlukast (−) antiasthmatic9.74.3a7.6a
    Ziprasidone (0) antidepressant3.6
    Zolpidem (0) sedative, anticonvulsant0.15

    • c.n.d., charge not determined; GI, gastrointestinal; n.t.d., no transport detected under the employed experimental conditions.

    • ↵a Uptake measurements performed in presence of an outwardly directed proton gradient.

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Review ArticleReview Article

Organic Cation Transporters

Hermann Koepsell
Pharmacological Reviews January 1, 2020, 72 (1) 253-319; DOI: https://doi.org/10.1124/pr.118.015578
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