Amino acids in transmembrane helix 1 confer major functional differences between human and mouse orthologs of the polyspecific membrane transporter OCT1

Abstract

Organic cation transporter 1 (OCT1) is a membrane transporter that affects hepatic uptake of cationic and weakly basic drugs. OCT1 transports structurally highly diverse substrates. The mechanisms conferring this polyspecificity are unknown. Here, we analyzed differences in transport kinetics between human and mouse OCT1 orthologs to identify amino acids that contribute to the polyspecificity of OCT1. Following stable transfection of HEK293 cells, we observed more than twofold differences in the transport kinetics of 22 out of 28 tested substrates. We found that the β2-adrenergic drug fenoterol was transported with eightfold higher affinity but at ninefold lower capacity by human OCT1. In contrast, the anticholinergic drug trospium was transported with 11-fold higher affinity but at ninefold lower capacity by mouse Oct1. Using human–mouse chimeric constructs and site-directed mutagenesis, we identified nonconserved amino acids Cys36 and Phe32 as responsible for the species-specific differences in fenoterol and trospium uptake. Substitution of Cys36 (human) to Tyr36 (mouse) caused a reversal of the affinity and capacity of fenoterol but not trospium uptake. Substitution of Phe32 to Leu32 caused reversal of trospium but not fenoterol uptake kinetics. Comparison of the uptake of structurally similar β2-adrenergics and molecular docking analyses indicated the second phenol ring, 3.3 to 4.8 Å from the protonated amino group, as essential for the affinity for fenoterol conferred by Cys36. This is the first study to report single amino acids as determinants of OCT1 polyspecificity. Our findings suggest that structure–function data of OCT1 is not directly transferrable between substrates or species. Organic cation transporter 1 (OCT1) is a membrane transporter that affects hepatic uptake of cationic and weakly basic drugs. OCT1 transports structurally highly diverse substrates. The mechanisms conferring this polyspecificity are unknown. Here, we analyzed differences in transport kinetics between human and mouse OCT1 orthologs to identify amino acids that contribute to the polyspecificity of OCT1. Following stable transfection of HEK293 cells, we observed more than twofold differences in the transport kinetics of 22 out of 28 tested substrates. We found that the β2-adrenergic drug fenoterol was transported with eightfold higher affinity but at ninefold lower capacity by human OCT1. In contrast, the anticholinergic drug trospium was transported with 11-fold higher affinity but at ninefold lower capacity by mouse Oct1. Using human–mouse chimeric constructs and site-directed mutagenesis, we identified nonconserved amino acids Cys36 and Phe32 as responsible for the species-specific differences in fenoterol and trospium uptake. Substitution of Cys36 (human) to Tyr36 (mouse) caused a reversal of the affinity and capacity of fenoterol but not trospium uptake. Substitution of Phe32 to Leu32 caused reversal of trospium but not fenoterol uptake kinetics. Comparison of the uptake of structurally similar β2-adrenergics and molecular docking analyses indicated the second phenol ring, 3.3 to 4.8 Å from the protonated amino group, as essential for the affinity for fenoterol conferred by Cys36. This is the first study to report single amino acids as determinants of OCT1 polyspecificity. Our findings suggest that structure–function data of OCT1 is not directly transferrable between substrates or species. Organic cation transporter 1 (OCT1, official gene nomenclature name: SLC22A1) is strongly and almost exclusively expressed at the sinusoidal membrane of human hepatocytes (1Nies A.T. Koepsell H. Winter S. Burk O. Klein K. Kerb R. Zanger U.M. Keppler D. Schwab M. Schaeffeler E. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver.Hepatology (Baltimore, Md.). 2009; 50: 1227-1240Crossref PubMed Scopus (287) Google Scholar, 2Tzvetkov M.V. Dos Santos Pereira J.N. Meineke I. Saadatmand A.R. Stingl J.C. Brockmöller J. Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration.Biochem. Pharmacol. 2013; 86: 666-678Crossref PubMed Scopus (135) Google Scholar, 3Wang L. Prasad B. Salphati L. Chu X. Gupta A. Hop C.E.C.A. Evers R. Unadkat J.D. Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics.Drug Metab. Dispos. 2015; 43: 367-374Crossref PubMed Scopus (122) Google Scholar, 4Beaudoin J.J. Brouwer K.L.R. Malinen M.M. Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside.Pharmacol. Ther. 2020; 211: 107542Crossref PubMed Scopus (18) Google Scholar). Genetically determined loss or reduction of OCT1 activity leads to substantial changes in pharmacokinetics or hepatic concentrations of drugs in humans (2Tzvetkov M.V. Dos Santos Pereira J.N. Meineke I. Saadatmand A.R. Stingl J.C. Brockmöller J. Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration.Biochem. Pharmacol. 2013; 86: 666-678Crossref PubMed Scopus (135) Google Scholar, 5Shu Y. Brown C. Castro R.A. Shi R.J. Lin E.T. Owen R.P. 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PubMed Scopus Google Scholar, A. A.T. K.M. of organic cation transporter 1 (OCT1) substrates in and in hepatic Metab. Dispos. 2020; PubMed Google Scholar). of polyspecificity. of structurally diverse are OCT1 substrates R. C. A. L. L. of substrates and of uptake by human organic cation transporters 1 and 2013; PubMed Scopus Google Scholar, B. J. of drugs and by human in and Pharmacol. PubMed Scopus Google Scholar). substrates are as and and as (2Tzvetkov M.V. Dos Santos Pereira J.N. Meineke I. Saadatmand A.R. Stingl J.C. Brockmöller J. Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration.Biochem. Pharmacol. 2013; 86: 666-678Crossref PubMed Scopus (135) Google Scholar, 5Shu Y. Brown C. Castro R.A. Shi R.J. Lin E.T. Owen R.P. Sheardown S.A. Yue L. Burchard E.G. Brett C.M. Giacomini K.M. Effect of genetic variation in the organic cation transporter 1, OCT1, Pharmacol. Ther. PubMed Scopus Google Scholar, M.V. D. Meineke I. D. I. Koepsell H. Brockmöller J. The of genetic polymorphisms in the organic cation transporters OCT1, and OCT3 the of Pharmacol. Ther. 2009; 86: PubMed Scopus Google Scholar, M.V. J. S. S. Brockmöller J. and and to fenoterol in with OCT1 Pharmacol. Ther. PubMed Scopus Google Scholar, Y. H. Y. of organic cation transporter 1 in hepatic and of Pharmacol. Ther. PubMed Scopus Google Scholar, B. J. of drugs and by human in and Pharmacol. PubMed Scopus Google Scholar, L. Y. X. S. L. Lin Y. K.M. J. J. is a transporter that hepatic and is a of S. A. PubMed Scopus Google Scholar, J. Brockmöller J. J. M.V. X. as substrates and of human organic cation transporters of the and the PubMed Scopus Google Scholar). The amino acids in of the OCT1 substrates and conferring OCT1 polyspecificity are of OCT1 or a transporter is and the that are with than amino to OCT1 H. Organic cation transporters in and 2020; PubMed Scopus Google Scholar). to identify with OCT1 X. A. Y. A. Giacomini K.M. of and of the organic cation transporter 1 PubMed Scopus Google Scholar, B. J.N. of transport the substrate Pharmacol. PubMed Scopus Google data by site-directed of single amino acids are essential to the of The data OCT1 are rat and substrates and C. A. Koepsell H. of the cation transporter is by of to Pharmacol. PubMed Scopus Google Scholar, C. Koepsell H. affinity for of rat organic cation transporters and amino acids the substrate Pharmacol. PubMed Scopus Google Scholar, Koepsell H. organic cation transporter 1 for substrate Pharmacol. PubMed Scopus Google Scholar, C. D. Koepsell H. acids for substrate affinity of rat organic cation transporter 1 the substrate in a from the of Pharmacol. PubMed Scopus Google Scholar, A. D. C. Koepsell H. of in rat organic cation transporters and for transport activity and substrate J. PubMed Scopus Google Scholar, C. A. Koepsell H. amino acids in the of the substrate of organic cation transporter 1 with and Pharmacol. 2009; PubMed Scopus Google Scholar). in humans to in identified as essential for with the of and OCT1 substrates C. A. Koepsell H. of the cation transporter is by of to Pharmacol. PubMed Scopus Google Scholar). This in H. A. M. A. of a 2013; PubMed Scopus Google and this for substrates was to identify OCT1 X. A. Y. A. Giacomini K.M. of and of the organic cation transporter 1 PubMed Scopus Google Scholar). OCT1 is to that between substrates H. and by organic cation PubMed Google Scholar, H. in organic cation transporters to identify of PubMed Scopus Google Scholar). acids identified to in substrate but substrates in rat C. D. Koepsell H. acids for substrate affinity of rat organic cation transporter 1 the substrate in a from the of Pharmacol. PubMed Scopus Google Scholar, C. A. Koepsell H. amino acids in the of the substrate of organic cation transporter 1 with and Pharmacol. 2009; PubMed Scopus Google Scholar, H. and by organic cation PubMed Google Scholar, H. in organic cation transporters to identify of PubMed Scopus Google Scholar). differences in the expression of OCT1 between human and mouse are J.C. A. I. S. C. Koepsell H. and of human organic cation PubMed Scopus Google Scholar, L. A.T. S. Giacomini K.M. and expression of a human organic cation Pharmacol. PubMed Scopus Google Scholar, K. C. and expression of a mouse organic cation (Baltimore, PubMed Scopus Google Scholar, A. R. A. Koepsell H. Organic cation transporter of is in PubMed Scopus Google is differences in transport kinetics and substrate in substrate between human and mouse A.T. Giacomini K.M. and differences between and human organic cation transporters Pharmacol. Ther. Google Scholar). The of mouse and human OCT1 in amino and is of differences in OCT1 A.T. Giacomini K.M. and differences between and human organic cation transporters Pharmacol. Ther. Google a of substrates in the mechanisms of the The of this study was to differences in OCT1 between the by the transport kinetics of a of substrates between human and mouse OCT1. we to identify or single amino acids in the OCT1 that the The from this study to identify amino acids in substrate of OCT1 and to the mechanisms conferring OCT1 polyspecificity. we the uptake of and between human and mouse OCT1 human to mouse or human The to expression and of human and mouse OCT1 A. S. C. J. S. Brockmöller J. B. M.V. in and uptake between human and mouse organic cation transporter determinants and for Metab. Dispos. 2020; PubMed Google Scholar). differences in the uptake kinetics between human and mouse OCT1 orthologs 1 and The differences observed in the capacity and in the affinity of substrate uptake by human and mouse in as for single human mouse not determined not to in in a as for single human mouse not determined not to the observed differences in affinity the substrates tested into The first substrates with a higher affinity of human than of mouse OCT1. This is by was transported with higher affinity by human than by mouse OCT1 and and This was with lower human OCT1 a transporter of fenoterol and mouse and The second substrates with a higher affinity of mouse than of human OCT1. This not is by trospium but and OCT1 a higher capacity and lower affinity for trospium than mouse 1, and 1 and and human OCT1 is a and mouse is a transporter of trospium we observed a substrates with substantial differences in as and mouse higher affinity with human OCT1. and transport by human OCT1 1 and the higher affinity of mouse was not with lower In contrast, for mouse higher affinity and higher capacity for the substrates we for the mechanisms the differences in the uptake of human and mouse and mouse OCT1 in amino acids of The amino acids are the to a for a single conferring the we a by and a of human–mouse chimeric OCT1 we chimeric constructs by the OCT1 into from the to the after from to and from to the the of fenoterol and trospium the substrates with the differences in the uptake between mouse and human OCT1, we identified the from to the first of as for the differences in fenoterol and in trospium uptake and human–mouse chimeric OCT1 constructs for conferring differences in fenoterol and trospium uptake between human and mouse OCT1. and of human–mouse chimeric OCT1 constructs with the or of human or mouse of the chimeric OCT1 constructs and fenoterol and trospium uptake and of chimeric OCT1 constructs with human OCT1 single of of the first the or the of mouse and fenoterol and trospium uptake. HEK293 and or and OCT1 with concentrations and or fenoterol or trospium for uptake was by the uptake of from the uptake of and and to the uptake by human and mouse OCT1. are and of at with human OCT1 in a human OCT1, organic cation transporter the conferring the differences in we chimeric constructs that of single of of the first the and the The uptake by single chimeric constructs was analyzed at single concentrations of fenoterol and trospium fenoterol and concentrations as differences between human and mouse OCT1 in the analyses of mouse into human OCT1 was the that fenoterol uptake with the human the of mouse into human OCT1 to the of was the that trospium uptake to or lower than mouse This to as a of the differences in uptake between human and mouse OCT1, and analyses In amino acids between human and mouse OCT1 We of amino acids with the amino of the in human and mouse OCT1 and analyzed fenoterol uptake. The of at to fenoterol uptake of human OCT1 by to from to to the uptake of the mouse The mouse fenoterol uptake by in uptake to human OCT1 of the amino acids in or the not affect fenoterol uptake and we HEK293 that human OCT1 and mouse and that this single amino was to the uptake kinetics of in of and affinity This the amino at in human and Tyr36 in mouse to the differences in fenoterol uptake. Cys36 as the amino that is responsible for the affinity of human OCT1, we to identify the the this we the uptake of fenoterol and structurally similar of the of β2-adrenergics between human and mouse OCT1. is of phenol by a amino group, a group, and a is structurally the in the of and the of the group, for the is of the between the phenol and with fenoterol but the second phenol and in the and of and the transport affinity between human and mouse OCT1, with the similar similar transport kinetics to with almost higher affinity of human OCT1 In contrast, the of the second phenol as in and to a in transport affinity to a more than higher affinity of mouse Oct1. the similar species-specific between fenoterol and In to affinity for was between human and mouse OCT1 This that the of phenol as in fenoterol and is not for higher affinity to the human OCT1, but the of the second to the of the amino the differences in the uptake of and 1 and In with the in human and in mouse OCT1 not affect the affinity for with the of fenoterol uptake a of Cys36 with the second phenol of we of of human OCT1 from the docking to study in the between and in human OCT1. to identify by with higher with a at the in of to a of with human OCT1, leads to a of fenoterol by by of the in In the the of the is with and is with the In the with the of the The in fenoterol is by a with as as a with The second phenol to in a of with the of and the Cys36 in this a to chimeric constructs to as of the differences in trospium uptake between human and mouse OCT1 and to we analyzed the of single amino in trospium uptake. The of at to in human OCT1 trospium uptake by to lower than the uptake of mouse Oct1. The in mouse trospium uptake by This to that the uptake of the human at the concentrations by In to not affect uptake of the of amino or the not affect the uptake of trospium and and Substitution of and not affect fenoterol uptake and and strongly of this amino We HEK293 that human OCT1 and mouse the HEK293 the and and This the amino at in human and Leu32 in mouse to the differences in trospium uptake. In this we report substantial differences in the substrate between human and mouse OCT1 of 28 substrates tested twofold or higher differences in OCT1 affinity This the polyspecificity of OCT1 and for of OCT1 data from mouse to species-specific variability in OCT1 as a for of the OCT1 transporter with a and chimeric constructs by site-directed mutagenesis, we to identify single amino that to the differences in affinity between human and mouse OCT1 was the substrate with the affinity of human OCT1 in this study and is the OCT1 substrates with the affinity in B. J. of drugs and by human in and Pharmacol. PubMed Scopus Google Scholar). We to identify a single amino (human) to Tyr36 was to the uptake kinetics of fenoterol between human and mouse and to fenoterol a substrate of affinity in human OCT1. trospium was the substrates transported with the affinity by mouse in this In this we to identify a single amino between the (mouse) to Phe32 was to the differences in transport kinetics and to trospium a substrate of affinity in mouse Oct1. the of this study the first for of amino acids in in OCT1 substrate The of the analyses in the and C. Koepsell H. affinity for of rat organic cation transporters and amino acids the substrate Pharmacol. PubMed Scopus Google Scholar, C. D. Koepsell H. acids for substrate affinity of rat organic cation transporter 1 the substrate in a from the of Pharmacol. PubMed Scopus Google Scholar). The is in in is to essential for OCT1 cation H. Organic cation transporters in and 2020; PubMed Scopus Google Scholar, X. A. Y. A. Giacomini K.M. of and of the organic cation transporter 1 PubMed Scopus Google Scholar, C. A. Koepsell H. of the cation transporter is by of to Pharmacol. PubMed Scopus Google Scholar, D. The human organic cation transporter OCT1 and as a for drug Metab. PubMed Scopus Google Scholar, organic cation into the substrate Pharmacol. PubMed Scopus Google Scholar). The amino acids Phe32 and Cys36 in as in OCT1 X. A. Y. A. Giacomini K.M. of and of the organic cation transporter 1 PubMed Scopus Google Scholar, B. J.N. of transport the substrate Pharmacol. PubMed Scopus Google Scholar). In the amino acids identified by in not and more than amino acids to of Cys36 and Phe32 strongly The to substantial differences in the affinity for fenoterol and the structurally but not affect the affinity for trospium or for β2-adrenergics and and Substitution of affected trospium but not fenoterol kinetics. Cys36 and Phe32 are in in but affect substrates in a This that mechanisms conferring polyspecificity. The amino acids Cys36 and Tyr36 as as Phe32 and Leu32 OCT1 orthologs Cys36 is in human and the Tyr36 in mouse is of the orthologs In contrast, Phe32 is for and of amino acids in OCT1 but for substrates and S. C.M. M.V. Koepsell H. of rat organic cation transporter of in the by of substrates and Pharmacol. PubMed Scopus Google Scholar). of as the of of This to the substrates and to the polyspecificity of OCT1 with a more substrates drugs or The differences in uptake kinetics for fenoterol and trospium observed between human and mouse OCT1 in are not to to substantial differences in the pharmacokinetics in the species. The for this is that the of affinity and transport capacity at a more than eightfold in transport affinity differences in transport capacity in the to almost OCT1 for OCT1 orthologs the uptake of human and mouse OCT1 at concentrations we not differences in for fenoterol for trospium tested concentrations are the for fenoterol M.V. J. S. S. Brockmöller J. and and to fenoterol in with OCT1 Pharmacol. Ther. PubMed Scopus Google and for trospium M. C. D. C. E. M. between trospium and substrates of organic cation transporters in human Pharmacol. 2020; PubMed Scopus Google but that the of differences in the uptake at lower of this is that data the of the hepatic uptake of fenoterol in A. A.T. K.M. of organic cation transporter 1 (OCT1) substrates in and in hepatic Metab. Dispos. 2020; PubMed Google OCT1 in In to fenoterol and differences in the between human and mouse OCT1 observed for substrates of and by A. S. C. J. S. Brockmöller J. B. M.V. in and uptake between human and mouse organic cation transporter determinants and for Metab. Dispos. 2020; PubMed Google Scholar). In this the of that are to differences in the was to the β2-adrenergic drugs and the substrate is of as not to and a of The uptake of substrates by mouse and of OCT1 in humans and the of the substrates mouse a higher 1 and hepatic uptake or uptake by The as and not transported at by human OCT1 but uptake by mouse Oct1. in substrate between for transporters as and for Y. H. K. S. M. between pharmacokinetics of in and that in humans is caused by of to a Google Scholar, X. K. Evers R. differences in drug transporters and for findings to Metab. 2013; PubMed Scopus Google Scholar, and of Metab. Dispos. Google Scholar, C. and Scholar, S. Y. M. differences of in of rat and PubMed Scopus Google Scholar). Our data suggest that of OCT1 for by in of to Our study that to the of with are analyzed X. A. Y. A. Giacomini K.M. of and of the organic cation transporter 1 PubMed Scopus Google Scholar, J. L. R. for drug of the human organic cation transport PubMed Scopus Google Scholar, O. Brockmöller J. C. of substrates of OCT1 and Scopus Google analyses of with similar to identify single in the with OCT1. Here, we analyses the of β2-adrenergic drugs by single we the species-specific differences in the uptake for of β2-adrenergics we to to the second phenol as the of the with Cys36 and the affinity of human OCT1 for the of we observed that the affinity of human OCT1 for is not higher than the of mouse a second phenol This by the between the second phenol of and the amino with the in This that not the of a second but the between the second and the amino in the affinity for The identified between the second phenol of fenoterol and Cys36 in human OCT1 molecular docking we that the was observed in of the to the of docking and of was the the the of Cys36 for the of fenoterol with human OCT1 to In the molecular to more the the molecular docking that in to Phe32 with the second of fenoterol data Substitution of not affect fenoterol uptake Leu32 in a as for Phe32 amino by in docking to with the second of fenoterol is This was in a by L. O. Brockmöller J. M. for transport of fenoterol by the organic cation transporters 1 and Pharmacol. PubMed Scopus Google but for the of fenoterol In we report substantial differences in the uptake kinetics between human and mouse OCT1. substrates and β2-adrenergic drugs transported with higher by mouse than by human OCT1, pharmacokinetics and data OCT1 from to we to identify single amino acids that are strongly in of OCT1. Cys36 conferred the affinity of human OCT1 for fenoterol in a highly and Leu32 conferred the affinity of mouse for amino acids for OCT1 polyspecificity identified by a of human and mouse OCT1 This is in the mechanisms of OCT1 polyspecificity and that is to OCT1 orthologs and and trospium from and from was from and was from and from tested as substrates from in this study from and of or and for from and from from and from and in from and and from was from HEK293 human OCT1, mouse human–mouse chimeric OCT1, or human and mouse OCT1 by the and of in A. S. C. J. S. Brockmöller J. B. M.V. in and uptake between human and mouse organic cation transporter determinants and for Metab. Dispos. 2020; PubMed Google Scholar, M.V. Saadatmand A.R. K. Meineke I. R. Brockmöller J. of OCT1 polymorphisms the concentrations and of the and J. Scholar, R. J. S. Dos Santos Pereira J.N. R. Brockmöller J. M.V. genetic analyses variability in the loss of activity of the organic cation transporter 2015; PubMed Scopus Google Scholar). in with and at and and a of OCT1 in HEK293 cells, expression or human or mouse OCT1 constructs as A. S. C. J. S. Brockmöller J. B. M.V. in and uptake between human and mouse organic cation transporter determinants and for Metab. Dispos. 2020; PubMed Google Scholar, M.V. Saadatmand A.R. K. Meineke I. R. Brockmöller J. of OCT1 polymorphisms the concentrations and of the and J. Scholar, R. J. S. Dos Santos Pereira J.N. R. Brockmöller J. M.V. genetic analyses variability in the loss of activity of the organic cation transporter 2015; PubMed Scopus Google Scholar). chimeric OCT1 constructs the the of by PubMed Scopus Google and A. S. C. J. S. Brockmöller J. B. M.V. in and uptake between human and mouse organic cation transporter determinants and for Metab. Dispos. 2020; PubMed Google Scholar). into human or mouse OCT1 by site-directed the in constructs by of the of OCT1 transfection into HEK293 transfection of OCT1 constructs into HEK293 for uptake in with with of with the OCT1 of and to the transfection was by the of the and the for uptake to the in cells, in to the and as with uptake at and with the to as with 1 and the uptake was by of the was for and by with and with with or for or substrate concentrations as in the and to the of in the as the of PubMed Scopus Google Scholar). of substrate the was at for and of was to at The was with and between and into the with was to a with and a a of and concentrations of organic concentrations of substrates and this was into a was and the was in the of was into a and was in a with and of and of OCT1, HEK293 or OCT1 in with to with 1 for and with for at with for with for with for and with for 1 to with the in in a at mouse and and The after with for with the in for 1 to from and with for analyzed a with and the of J. I. E. M. S. C. S. B. K. for PubMed Scopus Google Scholar, J. E.T. for the of PubMed Scopus Google Scholar). The of J. R. A. M. O. K. R. A. A. A. C. A. with PubMed Scopus Google the of highly are the M. S. M. S. C. D. O. A. A. K. S. J. the of with PubMed Scopus Google The of human OCT1 was in from the and for molecular docking R. and docking with 2009; PubMed Scopus Google Scholar). The of was from in and the at was in to the was in and and the was in a was the of the by the identified in A. S. C. J. S. Brockmöller J. B. M.V. in and uptake between human and mouse organic cation transporter determinants and for Metab. Dispos. 2020; PubMed Google Scholar). a and for molecular docking R. and docking with 2009; PubMed Scopus Google Scholar). The of was to and a of for of the to The docking a the of the and the of the to the at Å by the by from to in are in a of in a for of a the of the observed as as to a highly and with The transport and determined by to the between human and mouse OCT1 the with or uptake between or more that human and mouse OCT1 and human–mouse chimeric OCT1 or OCT1 by 28 was data are this and This The that of with the of this We and for in and uptake We for the and for the in the of mouse and human orthologs and the of the We for the for This was by of the of of We for the from the and the of the of M. J. M. and M. M. J. M. and B. M. J. M. and S. M. J. M. and C. S. S. and B. M. J. B. and M. M. J. M. and M. M. J. M. S. and B. J. and M. M. J. B. and M. with and with

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