Li et al. interactions (Figure 1A; Table 1). Since OCT1 has an overlapping substrate spectrum with the apically localized export proteins MATE1 [gene symbol (Nies et al., 2011)] and P-glycoprotein [P-gp, MDR1; gene symbol (Nies et al., 2008; Misaka et al., 2016)], double-transfected cell models have been established (MDCK-OCT1-MATE1 or MDCK-OCT1-P-gp) for investigating the vectorial transport mediated by both proteins (Table 2). MATE1 and P-glycoprotein are both localized in the apical (canalicular) membrane of human hepatocytes and responsible for the export of substances out of the cells into bile (Thiebaut et al., 1987; Otsuka et al., 2005). When expressed together with OCT1 in MDCK cells grown as a monolayer, OCT1 localizes in the basolateral and MATE1 or P-gp in the apical membrane (Figure 1B). In this experimental setup, substrates of OCT1 and MATE1/P-gp applied to the basolateral compartment will be first taken up into the cells mediated by OCT1 and subsequently exported via MATE1 or P-gp into the apical compartment (Figure 1B). Therefore, these cell models can be used to study not only OCT1-mediated uptake into the cells, but also the vectorial transport of substances from the basolateral into the apical compartment mimicking the transport processes during the hepatobiliary elimination e.g. of drugs (Taghikhani et al., 2017). Moreover, the importance of uptake and efflux transporters for perpetrator disposition can be assessed (Mller et al., 2018b). In this review, we summarize transport data related to the hepatocellular uptake transporter OCT1 obtained by studies in different cell models. Furthermore, the advantages and disadvantages of these cell models will be addressed. TABLE 1 Substrates of OCT1 (drugs, drug metabolites, endogenous molecules, chemicals) studied in single-transfected cell lines. oocytes14.6 4.39 Zhang et al. (1997) 1-methyl-4-phenylpyridinium (MPP+)HEK29332 Grndemann et al. (2003) 1-methyl-4-phenylpyridinium (MPP+)HEK29325.0 Umehara et al. (2007) 1-n-pentylbiguanideHEK293100 Obianom et al. (2017) 2-(2,4-dichlorophenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2-(4-biphenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2,2-diphenylethyl-biguanideHEK29314 2.8 Obianom et al. (2017) 2,3-dihydro-1H-inden-2-yl-biguanideHEK293100 Obianom et al. (2017) 2-ehylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)HEK2931 Campbell et al. (2015) 3-methoxymorphinanHEK2930.05C0.5 Meyer et al. (2019) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK2932.32 0.29 Ahlin et al. (2008) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK29321.2 Chen et al. (2017a) 4H-1-benzopyran-4-one-biguanideHEK293100 Obianom et al. (2017) Acebutol-(R)HEK29319.9 5.7 Jensen et al. (2020b) Acebutol-(S)HEK29321.0 2.5 Jensen et al. (2020b) Acetylcholine oocytes5 Lips et al. (2005) AciclovirS2151.2 22.1 Takeda et al. (2002) Aflatoxin B1S20.1 Tachampa et al. (2008) AlbuterolHEK2932.5 Hendrickx et al. (2013) AmifampridineHEK293508.1 247.3 Jensen et al. (2021) AmilorideHEK2932.5 Hendrickx et al. (2013) AmisulprideHEK29331.3 5.4 Dos Santos Pereira et al. (2014) AnisodineHEK2931C5 Chen et al. (2019) AR-H067637HEK29326 Matsson et al. (2013) AR-H069927HEK293116 Matsson et al. (2013) AtenololMDCK3080 Mimura et al. (2015) Atenolol racemateHEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK293201.9 33.1 Jensen et al. (2020b) Atenolol-(S)HEK2932.5 Hendrickx et al. (2013) Atenolol-(S)HEK293196.4 23.1 Jensen et al. (2020b) AtropineHEK2935.9 1.4 Chen et al. (2017b) Azidoprocainamide oocytes100.9 43.0 van Montfoort et al. (2001) BenzyltriethylammoniumHEK29338.6 9.9 Jensen et al. (2021) BerberineMDCK14.8 3.3 Nies et al. (2008) BerberrubineMDCK1.27 0.23 Li et al. (2016) BromosulfophthaleinHEK29313.6 2.6 Boxberger et al. (2018) ButylscopolamineHEK29323.4 2.3 Chen et al. (2017b) CimetidineHEK2932.5 Hendrickx et al. (2013) oocytes300 Gorboulev et al. (1997) NadololHEK2931C1000 Misaka et al. (2016) NaratriptanHEK2931000 Matthaei et al. (2016) N-ethyllidocaineHEK29351.4 15.4 Jensen et al. (2021) NitidineMDCK0.797 0.17 Li et al. (2014) NizatidineHEK2932.5 Hendrickx et al. (2013) N-methyladenosineHEK293100 Miyake et al. (2019) N-methylquinidine oocytes11.5 2.1 van Montfoort et al. (2001) N-methylquinine oocytes19.5 7.3 van Montfoort et al. (2001) NorfentanylHEK2937.7 0.8 Meyer et al. (2019) NorlevorphanolHEK2930.05C0.5 Meyer et al. (2019) NoroxycodoneHEK29320.05 6.5 Meyer et al. (2019) NorphenylephrineHEK293994.1 316.5 Jensen et al. (2021) OctopamineHEK293388.6 246.4 Jensen et al. (2021) O-desmethyl tramadolHEK2931 Tzvetkov et al. (2011) Orciprenaline-(R)HEK293780.5 285.9 Jensen et al. (2020b) Orciprenaline-(S)HEK293808.8 292.6 Jensen et al. (2020b) OxaliplatinMDCK10 Lovejoy et al. (2008) OxaliplatinHEK2931000 Yonezawa et al. (2006) OxibutyninHEK2938.82 0.44 Wenge et.As expected, the transcellular transport was highest at extracellular pH 6.5, whereas intracellular accumulation was lowest at this pH, demonstrating that OCT1 and MATE1 play an important role in the transcellular transport of trospium. Ceckova et al. (e.g., HEK-OCT1 cells) recombinantly overexpressing OCT1 were established to study OCT1-mediated transport, to calculate transport parameters (e.g., Km values), to investigate the impact of genetic variations and to evaluate OCT1-mediated drug-drug interactions (Figure 1A; Table 1). Since OCT1 has an overlapping substrate spectrum with the apically localized export proteins MATE1 [gene symbol (Nies et al., 2011)] and P-glycoprotein [P-gp, MDR1; gene symbol (Nies et al., 2008; Misaka et al., 2016)], double-transfected cell models have been established (MDCK-OCT1-MATE1 or MDCK-OCT1-P-gp) for investigating the vectorial transport mediated by both proteins (Table 2). MATE1 and P-glycoprotein are both localized in the apical (canalicular) membrane of human hepatocytes and responsible for the export of substances out of the cells into bile (Thiebaut et al., 1987; Otsuka et al., 2005). When expressed together with OCT1 in MDCK cells grown as a monolayer, OCT1 localizes in the basolateral and MATE1 or P-gp in the apical membrane (Figure 1B). In this experimental setup, substrates of OCT1 and MATE1/P-gp applied to the basolateral compartment will be first taken up into the cells mediated by OCT1 and subsequently exported via MATE1 or P-gp into the apical compartment (Figure 1B). Therefore, these cell models can be used to study not only OCT1-mediated uptake into the cells, but also the vectorial transport of substances from your basolateral into the apical compartment mimicking the transport processes during the hepatobiliary removal e.g. of medicines (Taghikhani et al., 2017). Moreover, the importance of uptake and efflux transporters for perpetrator disposition can be assessed (Mller et al., 2018b). With this review, we summarize transport data related to the hepatocellular uptake transporter OCT1 acquired by studies in different cell models. Furthermore, the advantages and disadvantages of these cell models will be tackled. TABLE 1 Substrates of OCT1 (medicines, drug metabolites, endogenous molecules, chemicals) analyzed in single-transfected cell lines. oocytes14.6 4.39 Zhang et al. (1997) 1-methyl-4-phenylpyridinium (MPP+)HEK29332 Grndemann et al. (2003) 1-methyl-4-phenylpyridinium (MPP+)HEK29325.0 Umehara et al. (2007) 1-n-pentylbiguanideHEK293100 Obianom et al. (2017) 2-(2,4-dichlorophenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2-(4-biphenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2,2-diphenylethyl-biguanideHEK29314 2.8 Obianom et al. (2017) 2,3-dihydro-1H-inden-2-yl-biguanideHEK293100 Obianom et al. (2017) 2-ehylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)HEK2931 Campbell et al. (2015) 3-methoxymorphinanHEK2930.05C0.5 Meyer et al. (2019) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK2932.32 0.29 Ahlin et al. (2008) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK29321.2 Chen et al. (2017a) 4H-1-benzopyran-4-one-biguanideHEK293100 Obianom et al. (2017) Acebutol-(R)HEK29319.9 5.7 Jensen et al. (2020b) Acebutol-(S)HEK29321.0 2.5 Jensen et al. (2020b) Acetylcholine oocytes5 Lips et al. (2005) AciclovirS2151.2 22.1 Takeda et al. (2002) Aflatoxin B1S20.1 Tachampa et al. (2008) AlbuterolHEK2932.5 Hendrickx et al. (2013) AmifampridineHEK293508.1 247.3 Jensen et al. (2021) AmilorideHEK2932.5 Hendrickx et al. (2013) AmisulprideHEK29331.3 5.4 Dos Santos Pereira et al. (2014) AnisodineHEK2931C5 Chen et al. (2019) AR-H067637HEK29326 Matsson et al. (2013) AR-H069927HEK293116 Rabbit Polyclonal to EDG4 Matsson et al. (2013) AtenololMDCK3080 Mimura et al. (2015) Atenolol racemateHEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK293201.9 33.1 Jensen et al. (2020b) Atenolol-(S)HEK2932.5 Hendrickx et al. (2013) Atenolol-(S)HEK293196.4 23.1 Jensen et al. (2020b) AtropineHEK2935.9 1.4 Chen et al. (2017b) Azidoprocainamide oocytes100.9 43.0 vehicle Montfoort et al. (2001) BenzyltriethylammoniumHEK29338.6 9.9 Jensen et al. (2021) BerberineMDCK14.8 3.3 Nies et al. (2008) BerberrubineMDCK1.27 0.23 Li et al. (2016) BromosulfophthaleinHEK29313.6 2.6 Boxberger et al. (2018) ButylscopolamineHEK29323.4 2.3 Chen et al. (2017b) CimetidineHEK2932.5 Hendrickx et al. (2013) oocytes300 Gorboulev et al. (1997) NadololHEK2931C1000 Misaka et al. (2016) NaratriptanHEK2931000 Matthaei et al. (2016) N-ethyllidocaineHEK29351.4 15.4 Jensen et al. (2021) NitidineMDCK0.797 0.17 Li et al. (2014) NizatidineHEK2932.5 Hendrickx et al. (2013) N-methyladenosineHEK293100 Miyake et al. (2019) N-methylquinidine oocytes11.5 2.1 vehicle Montfoort et al. (2001) N-methylquinine oocytes19.5 7.3 vehicle Montfoort et al. (2001) NorfentanylHEK2937.7 0.8 Meyer et al. (2019) NorlevorphanolHEK2930.05C0.5 Meyer et al. (2019) NoroxycodoneHEK29320.05 6.5 Meyer et al. (2019) NorphenylephrineHEK293994.1 316.5 Jensen et al. (2021) OctopamineHEK293388.6 246.4 Jensen et al. (2021) O-desmethyl tramadolHEK2931 Tzvetkov et al. (2011) Orciprenaline-(R)HEK293780.5 285.9 Jensen et.Consequently, these cell models can be used to study not only OCT1-mediated uptake into the cells, but also the vectorial transport of substances from your basolateral into the apical compartment mimicking the transport processes during the hepatobiliary elimination e.g. liver and localized in the basolateral membrane of human being hepatocytes (Gorboulev et al., 1997; Nies et al., 2008). It mediates the uptake of several endogenous and exogenous compounds and medicines (Table 1). Single-transfected cell models (e.g., HEK-OCT1 cells) recombinantly overexpressing OCT1 were founded to study OCT1-mediated transport, to calculate transport guidelines (e.g., Km values), to investigate the effect of genetic variations and to evaluate OCT1-mediated drug-drug relationships (Number 1A; Table 1). Since OCT1 has an overlapping substrate spectrum with the apically localized export proteins MATE1 [gene sign (Nies et al., 2011)] and P-glycoprotein [P-gp, MDR1; gene sign (Nies et al., 2008; Misaka et al., 2016)], double-transfected cell models have been founded (MDCK-OCT1-MATE1 or MDCK-OCT1-P-gp) for investigating the vectorial transport mediated by both proteins (Table 2). MATE1 and P-glycoprotein are both localized in the apical (canalicular) membrane of human being hepatocytes and responsible for the export of substances out of the cells into bile (Thiebaut et al., 1987; Otsuka et BAY 87-2243 al., 2005). When indicated together with OCT1 in MDCK cells cultivated like a monolayer, OCT1 localizes in the basolateral and MATE1 or P-gp in the apical membrane (Number 1B). With this experimental setup, substrates of OCT1 and MATE1/P-gp applied to the basolateral compartment will be 1st taken up into the cells mediated by OCT1 and consequently exported via MATE1 or P-gp into the apical compartment (Number 1B). Consequently, these cell models can be used to study not only OCT1-mediated uptake into the cells, but also the vectorial transport of substances from your basolateral into the apical compartment mimicking the transport processes during the hepatobiliary removal e.g. of medicines (Taghikhani et al., 2017). Moreover, the importance of uptake and efflux transporters for perpetrator disposition can be assessed (Mller et al., 2018b). With this review, we summarize transport data related to the hepatocellular uptake transporter OCT1 acquired by studies in different cell models. Furthermore, the advantages and disadvantages of these cell models will be tackled. TABLE 1 Substrates of OCT1 (medicines, drug metabolites, endogenous molecules, chemicals) analyzed in single-transfected cell lines. oocytes14.6 4.39 Zhang et al. (1997) 1-methyl-4-phenylpyridinium (MPP+)HEK29332 Grndemann et al. (2003) 1-methyl-4-phenylpyridinium (MPP+)HEK29325.0 Umehara et al. (2007) 1-n-pentylbiguanideHEK293100 Obianom et al. (2017) 2-(2,4-dichlorophenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2-(4-biphenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2,2-diphenylethyl-biguanideHEK29314 2.8 Obianom et al. (2017) 2,3-dihydro-1H-inden-2-yl-biguanideHEK293100 Obianom et al. (2017) 2-ehylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)HEK2931 Campbell et al. (2015) 3-methoxymorphinanHEK2930.05C0.5 Meyer et al. (2019) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK2932.32 0.29 Ahlin et al. (2008) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK29321.2 Chen et al. (2017a) 4H-1-benzopyran-4-one-biguanideHEK293100 Obianom et al. (2017) Acebutol-(R)HEK29319.9 5.7 Jensen et al. (2020b) Acebutol-(S)HEK29321.0 2.5 Jensen et al. (2020b) Acetylcholine oocytes5 Lips et al. (2005) AciclovirS2151.2 22.1 Takeda et al. (2002) Aflatoxin B1S20.1 Tachampa et al. (2008) AlbuterolHEK2932.5 Hendrickx et al. (2013) AmifampridineHEK293508.1 247.3 Jensen et al. (2021) AmilorideHEK2932.5 Hendrickx et al. (2013) AmisulprideHEK29331.3 5.4 Dos Santos Pereira et al. (2014) AnisodineHEK2931C5 Chen et al. (2019) AR-H067637HEK29326 Matsson et al. (2013) AR-H069927HEK293116 Matsson et al. (2013) AtenololMDCK3080 Mimura et al. (2015) Atenolol racemateHEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK293201.9 33.1 Jensen et al. (2020b) Atenolol-(S)HEK2932.5 Hendrickx et BAY 87-2243 al. (2013) Atenolol-(S)HEK293196.4 23.1 Jensen et al. (2020b) AtropineHEK2935.9 1.4 Chen et al. (2017b) Azidoprocainamide oocytes100.9 43.0 vehicle Montfoort et al. (2001) BenzyltriethylammoniumHEK29338.6 9.9 Jensen et al. (2021) BerberineMDCK14.8 3.3 Nies et al. (2008) BerberrubineMDCK1.27 0.23 Li et al. (2016) BromosulfophthaleinHEK29313.6 2.6 Boxberger et al. (2018) ButylscopolamineHEK29323.4 2.3 Chen et al. (2017b) CimetidineHEK2932.5 Hendrickx et al. (2013) oocytes300 Gorboulev et al. (1997) NadololHEK2931C1000 Misaka et al. (2016) NaratriptanHEK2931000 Matthaei et al. (2016) N-ethyllidocaineHEK29351.4 15.4 Jensen et al. (2021) NitidineMDCK0.797 0.17 Li et al. (2014) NizatidineHEK2932.5 Hendrickx et al. (2013) N-methyladenosineHEK293100 Miyake et al. (2019) N-methylquinidine oocytes11.5 2.1 vehicle Montfoort et al. (2001) N-methylquinine oocytes19.5 7.3 vehicle Montfoort et al. (2001) NorfentanylHEK2937.7 0.8 Meyer et al. (2019) NorlevorphanolHEK2930.05C0.5 Meyer et al. (2019) NoroxycodoneHEK29320.05 6.5 Meyer et al. (2019) NorphenylephrineHEK293994.1 316.5 Jensen et al. (2021) OctopamineHEK293388.6 246.4 Jensen et al. (2021) O-desmethyl tramadolHEK2931 Tzvetkov et al. (2011) Orciprenaline-(R)HEK293780.5 285.9 Jensen.Subsequent to the identification of berberine, a quaternary isoquinoline alkaloid, as an OCT1 and OCT2 substrate, the authors used the MDCK-OCT1-P-gp cell line to analyze the transcellular transport of this substance. family member OCT1 (gene sign cell models. OCT1 is mainly indicated in liver and localized in the basolateral membrane of human hepatocytes (Gorboulev et al., 1997; Nies et al., 2008). It mediates the uptake of several endogenous and exogenous compounds and drugs (Table 1). Single-transfected cell models (e.g., HEK-OCT1 cells) recombinantly overexpressing OCT1 were established to study OCT1-mediated transport, to calculate transport parameters (e.g., Km values), to investigate the impact of genetic variations and to evaluate OCT1-mediated drug-drug interactions (Physique 1A; Table 1). Since OCT1 has an overlapping substrate spectrum with the apically localized export proteins MATE1 [gene sign (Nies et al., 2011)] and P-glycoprotein [P-gp, MDR1; gene sign (Nies et al., 2008; Misaka et al., 2016)], double-transfected cell models have been established (MDCK-OCT1-MATE1 or MDCK-OCT1-P-gp) for investigating the vectorial transport mediated by both proteins (Table 2). MATE1 and P-glycoprotein are both localized in the apical (canalicular) membrane of human hepatocytes and responsible for the export of substances out of the cells into bile (Thiebaut et al., 1987; Otsuka et al., 2005). When expressed together with OCT1 in MDCK cells produced as a monolayer, OCT1 localizes in the basolateral and MATE1 or P-gp in the apical membrane (Physique 1B). In this experimental setup, substrates of OCT1 and MATE1/P-gp applied to the basolateral compartment will be first taken up into the cells mediated by OCT1 and subsequently exported via MATE1 or P-gp into the apical compartment (Physique 1B). Therefore, these cell models can be used to study not only OCT1-mediated uptake into the cells, but also the vectorial transport of substances from your basolateral into the apical compartment mimicking the transport processes during the hepatobiliary removal e.g. of drugs (Taghikhani et al., 2017). Moreover, the importance of uptake and efflux transporters for perpetrator disposition can be assessed (Mller et al., 2018b). In this review, we summarize transport data related to the hepatocellular uptake transporter OCT1 obtained by studies in different cell models. Furthermore, the advantages and disadvantages of these cell models will be resolved. TABLE 1 Substrates of OCT1 (drugs, drug metabolites, endogenous molecules, chemicals) analyzed in single-transfected cell lines. oocytes14.6 4.39 Zhang et al. (1997) 1-methyl-4-phenylpyridinium (MPP+)HEK29332 Grndemann et al. (2003) 1-methyl-4-phenylpyridinium (MPP+)HEK29325.0 Umehara et al. (2007) 1-n-pentylbiguanideHEK293100 Obianom et al. (2017) 2-(2,4-dichlorophenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2-(4-biphenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2,2-diphenylethyl-biguanideHEK29314 2.8 Obianom et al. (2017) 2,3-dihydro-1H-inden-2-yl-biguanideHEK293100 Obianom et al. (2017) 2-ehylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)HEK2931 Campbell et al. (2015) 3-methoxymorphinanHEK2930.05C0.5 Meyer et al. (2019) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK2932.32 0.29 Ahlin et al. (2008) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK29321.2 Chen et al. (2017a) 4H-1-benzopyran-4-one-biguanideHEK293100 Obianom et al. (2017) Acebutol-(R)HEK29319.9 5.7 Jensen et al. (2020b) Acebutol-(S)HEK29321.0 2.5 Jensen et al. (2020b) Acetylcholine oocytes5 Lips et al. (2005) AciclovirS2151.2 22.1 Takeda et al. (2002) Aflatoxin B1S20.1 Tachampa et al. (2008) AlbuterolHEK2932.5 Hendrickx et al. (2013) AmifampridineHEK293508.1 247.3 Jensen et al. (2021) AmilorideHEK2932.5 Hendrickx et al. (2013) AmisulprideHEK29331.3 5.4 Dos Santos Pereira et al. (2014) AnisodineHEK2931C5 Chen et al. (2019) AR-H067637HEK29326 Matsson et al. (2013) AR-H069927HEK293116 Matsson et al. (2013) AtenololMDCK3080 Mimura et al. (2015) Atenolol racemateHEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK293201.9 33.1 Jensen et al. (2020b) Atenolol-(S)HEK2932.5 Hendrickx et al. (2013) Atenolol-(S)HEK293196.4 23.1 Jensen et al. (2020b) AtropineHEK2935.9 1.4 Chen et al. (2017b) Azidoprocainamide oocytes100.9 43.0 van Montfoort et al. (2001) BenzyltriethylammoniumHEK29338.6 9.9 Jensen et al. (2021) BerberineMDCK14.8 3.3 Nies et al. (2008) BerberrubineMDCK1.27 0.23 Li et al. (2016) BromosulfophthaleinHEK29313.6 2.6 Boxberger et al. (2018) ButylscopolamineHEK29323.4 2.3 Chen et al. (2017b) CimetidineHEK2932.5 Hendrickx et al. (2013) oocytes300 Gorboulev et al. (1997) NadololHEK2931C1000 Misaka et al. (2016) NaratriptanHEK2931000 Matthaei et al. (2016) N-ethyllidocaineHEK29351.4 15.4 Jensen et al. (2021) NitidineMDCK0.797 0.17 Li et al. (2014) NizatidineHEK2932.5 Hendrickx et al. (2013) N-methyladenosineHEK293100 Miyake et al. (2019) N-methylquinidine oocytes11.5 2.1 van Montfoort et al. (2001) N-methylquinine oocytes19.5 7.3 van Montfoort et al. (2001) NorfentanylHEK2937.7 0.8 Meyer et al. (2019) NorlevorphanolHEK2930.05C0.5 Meyer et al. (2019) NoroxycodoneHEK29320.05 6.5 Meyer et al. (2019) NorphenylephrineHEK293994.1 316.5 Jensen et al. (2021) OctopamineHEK293388.6 246.4 Jensen et al. (2021) O-desmethyl tramadolHEK2931 Tzvetkov et al. (2011) Orciprenaline-(R)HEK293780.5 285.9 Jensen et al. (2020b) Orciprenaline-(S)HEK293808.8 292.6 Jensen et al. (2020b) OxaliplatinMDCK10 Lovejoy et al. (2008) OxaliplatinHEK2931000 Yonezawa et al. (2006) OxibutyninHEK2938.82 0.44 Wenge et al..The OCT1 substrate and/or inhibitor spectrum has intensively been studied by various groups [e.g., (Gorboulev et al., 1997; Ciarimboli et al., 2005; Wenge et al., 2011; Tzvetkov et al., 2013; Knop et al., 2015; Otter et al., 2017; Meyer et al., 2019; Jensen et al., 2020b; Koepsell, 2020)]. Single-transfected cell models have also been extensively used to study the influence of genetic polymorphisms in the gene on kinetic parameters of the OCT1-mediated transport (Kerb et al., 2002; Shu et al., 2003; Tzvetkov et al., 2011; Tzvetkov et al., 2013; Dos Santos Pereira et al., 2014; Matthaei et al., 2016; Meyer et al., 2017; Jensen et al., 2020b). hepatocytes (Gorboulev et al., 1997; Nies et al., 2008). It mediates the uptake of several endogenous and exogenous compounds and drugs (Table 1). Single-transfected cell models (e.g., HEK-OCT1 cells) recombinantly overexpressing OCT1 were established to study OCT1-mediated transport, to calculate transport parameters (e.g., Km values), to investigate the impact of genetic variations and to evaluate OCT1-mediated drug-drug interactions (Physique 1A; Table 1). Since OCT1 has an BAY 87-2243 overlapping substrate spectrum with the apically localized export proteins MATE1 [gene sign (Nies et al., 2011)] and P-glycoprotein [P-gp, MDR1; gene sign (Nies et al., 2008; Misaka et al., 2016)], double-transfected cell models have been established (MDCK-OCT1-MATE1 or MDCK-OCT1-P-gp) for investigating the vectorial transport mediated by both proteins (Table 2). MATE1 and P-glycoprotein are both localized in the apical (canalicular) membrane of human hepatocytes and responsible for the export of substances out of the cells into bile (Thiebaut et al., 1987; Otsuka et al., 2005). When expressed together with OCT1 in MDCK cells produced as a monolayer, OCT1 localizes in the basolateral and MATE1 or P-gp in the apical membrane (Physique 1B). In this experimental setup, substrates of OCT1 and MATE1/P-gp applied to the basolateral compartment will be first taken up into the cells mediated by OCT1 and subsequently exported via MATE1 or P-gp into the apical compartment (Shape 1B). Consequently, these cell versions may be used to research not merely OCT1-mediated uptake in to the cells, but also the vectorial transportation of substances through the basolateral in to the apical area mimicking the transportation processes through the hepatobiliary eradication e.g. of medicines (Taghikhani et al., 2017). Furthermore, the need for uptake and efflux transporters for perpetrator disposition could be evaluated (Mller et al., 2018b). With this review, we summarize transportation data linked to the hepatocellular uptake transporter OCT1 acquired by studies in various cell versions. Furthermore, advantages and drawbacks of the cell versions will be dealt with. TABLE 1 Substrates of OCT1 (medicines, medication metabolites, endogenous substances, chemicals) researched in single-transfected cell lines. oocytes14.6 4.39 Zhang et al. (1997) 1-methyl-4-phenylpyridinium (MPP+)HEK29332 Grndemann et al. (2003) 1-methyl-4-phenylpyridinium (MPP+)HEK29325.0 Umehara et al. (2007) 1-n-pentylbiguanideHEK293100 Obianom et al. (2017) 2-(2,4-dichlorophenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2-(4-biphenyl)ethyl-biguanideHEK293100 Obianom et al. (2017) 2,2-diphenylethyl-biguanideHEK29314 2.8 Obianom et al. (2017) 2,3-dihydro-1H-inden-2-yl-biguanideHEK293100 Obianom et al. (2017) 2-ehylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)HEK2931 Campbell et al. (2015) 3-methoxymorphinanHEK2930.05C0.5 Meyer et al. (2019) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK2932.32 0.29 Ahlin et al. (2008) 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+)HEK29321.2 Chen et al. (2017a) 4H-1-benzopyran-4-one-biguanideHEK293100 Obianom et al. (2017) Acebutol-(R)HEK29319.9 5.7 Jensen et al. (2020b) Acebutol-(S)HEK29321.0 2.5 Jensen et al. (2020b) Acetylcholine oocytes5 Lip area et al. (2005) AciclovirS2151.2 22.1 Takeda et al. (2002) Aflatoxin B1S20.1 Tachampa et al. (2008) AlbuterolHEK2932.5 Hendrickx et al. (2013) AmifampridineHEK293508.1 247.3 Jensen et al. (2021) AmilorideHEK2932.5 Hendrickx et al. (2013) AmisulprideHEK29331.3 5.4 Dos Santos Pereira et al. (2014) AnisodineHEK2931C5 Chen et al. (2019) AR-H067637HEK29326 Matsson et al. (2013) AR-H069927HEK293116 Matsson et al. (2013) AtenololMDCK3080 Mimura et al. (2015) Atenolol racemateHEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK2932.5 Hendrickx et al. (2013) Atenolol-(R)HEK293201.9 33.1 Jensen et al. (2020b) Atenolol-(S)HEK2932.5 Hendrickx et al. (2013) Atenolol-(S)HEK293196.4 23.1 Jensen et al. (2020b) BAY 87-2243 AtropineHEK2935.9 1.4 Chen et al. (2017b) Azidoprocainamide oocytes100.9 43.0 vehicle Montfoort et al. (2001) BenzyltriethylammoniumHEK29338.6 9.9 Jensen et al. (2021) BerberineMDCK14.8 3.3 Nies et al. (2008) BerberrubineMDCK1.27 0.23 Li et al. (2016) BromosulfophthaleinHEK29313.6 2.6 Boxberger et al. (2018) ButylscopolamineHEK29323.4 2.3 Chen et al. (2017b) CimetidineHEK2932.5 Hendrickx et al. (2013) oocytes300 Gorboulev et al. (1997) NadololHEK2931C1000 Misaka et al. (2016) NaratriptanHEK2931000 Matthaei et al. (2016) N-ethyllidocaineHEK29351.4 15.4 Jensen et al. (2021) NitidineMDCK0.797 0.17 Li et al. (2014) NizatidineHEK2932.5 Hendrickx et al. (2013) N-methyladenosineHEK293100 Miyake et al. (2019) N-methylquinidine oocytes11.5 2.1 vehicle Montfoort et al. (2001) N-methylquinine oocytes19.5 7.3 vehicle Montfoort et al. (2001) NorfentanylHEK2937.7 0.8 Meyer et al. (2019) NorlevorphanolHEK2930.05C0.5 Meyer et al. (2019) NoroxycodoneHEK29320.05 6.5 Meyer et al. (2019) NorphenylephrineHEK293994.1 316.5 Jensen et al. (2021) OctopamineHEK293388.6 246.4 Jensen et al. (2021) O-desmethyl tramadolHEK2931 Tzvetkov et al. (2011) Orciprenaline-(R)HEK293780.5 285.9 Jensen et al. (2020b) Orciprenaline-(S)HEK293808.8 292.6 Jensen et al. (2020b) OxaliplatinMDCK10 Lovejoy et al. (2008) OxaliplatinHEK2931000 Yonezawa et al. (2006) OxibutyninHEK2938.82 0.44 Wenge et al. (2011) OxophenomiumHEK2932.5 Hendrickx et.
