advanced drug delivery reviews - university of helsinki · recent advance in the pharmacogenomics...

Recent advance in the pharmacogenomics of human Solute CarrierTransporters (SLCs) in drug disposition☆

Fanfan Zhou a,⁎, Ling Zhu b, Ke Wang c, Michael Murray d

a Faculty of Pharmacy, University of Sydney, NSW 2006, Australiab Save Sight Institute, the University of Sydney, Sydney, NSW 2000, Australiac Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu Province, Chinad Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, NSW 2006, Australia

a b s t r a c ta r t i c l e i n f o

Article history:Received 6 April 2016Received in revised form 1 June 2016Accepted 8 June 2016Available online 16 June 2016

Drug pharmacokinetics is influenced by the function of metabolising enzymes and influx/efflux transporters. Ge-netic variability of these genes is known to impact on clinical therapies. Solute Carrier Transporters (SLCs) are theprimary influx transporters responsible for the cellular uptake of drugmolecules, which consequently, impact ondrug efficacy and toxicity. The Organic Anion Transporting Polypeptides (OATPs), Organic Anion Transporters(OATs) and Organic Cation Transporters (OCTs/OCTNs) are themost important SLCs involved in drug disposition.The information regarding the influence of SLC polymorphisms on drug pharmacokinetics is limited and remainsa hot topic of pharmaceutical research. This review summarises the recent advance in the pharmacogenomics ofSLCs with an emphasis on human OATPs, OATs and OCTs/OCTNs. Our current appreciation of the degree ofvariability in these transporters may contribute to better understanding the inter-patient variation of therapiesand thus, guide the optimisation of clinical treatments.

© 2016 Elsevier B.V. All rights reserved.

Keywords:Solute Carrier TransportersDrug pharmacokineticsPharmacogenomicsOrganic anion transporting polypeptidesOrganic anion transportersOrganic cation transporters

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222. Organic Anion Transporting Polypeptides (OATPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

2.1. OATP1A2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222.2. OATP1B1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.3. OATP1B3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.4. OATP2B1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.5. Other OATPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

3. Organic anion transporters (OATs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.1. OAT1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.2. OAT2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.3. OAT3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.4. OAT4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283.5. URAT1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283.6. Other OATs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

4. Organic cation transporters (OCTs/OCTNs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284.1. OCT1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284.2. OCT2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284.3. OCT3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304.4. OCTN1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314.5. OCTN2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314.6. OCT6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Advanced Drug Delivery Reviews 116 (2017) 21–36

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Drug Transporters: Molecular Mechanisms, Novel Modes of Regulations, and Therapeutic Strategies".⁎ Corresponding author at: Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia. Tel.: +61 2 9351 7461; fax: +61 2 9351 4391.

E-mail address: [email protected] (F. Zhou).

http://dx.doi.org/10.1016/j.addr.2016.06.0040169-409X/© 2016 Elsevier B.V. All rights reserved.

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5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

1. Introduction

Large inter-individual variability in drug response and toxicity hasbeen widely reported in most patient populations. Under the standarddosage, drug plasma concentration could vary N600 folds in two pa-tients of the samebodyweight. Genetic differences are likely the leadingcause of such variation [1–3]. Drug pharmacokinetic performancethat described as absorption, distribution, metabolism and excretion(ADME) in an organism, ismainly determined by the expression and ac-tivity of drug-metabolising enzymes and/or drug transporters. Alteredexpression/activity of drug-metabolising enzymes and transportersoften lead to variable drug response and toxicity in individuals.

Membrane transporters are classified as influx and efflux trans-porters. Influx transporters, primarily the Solute Carrier Transporters(SLCs) [4], mediate drug uptake into cells; while efflux transporters,principally the ATP-binding Cassette transporters (ABCs) are responsi-ble for moving drugs out of cells. Interplay of influx/efflux drugtransporters and drug-metabolising enzymes are essential to drugpharmacokinetics.

SLC superfamily includes more than 300 members, most of whichlocalised in the cell membrane. SLCs are expressed in a number ofhuman key tissues including the kidney, liver, intestine and brain,where they are crucial for maintaining body homeostasis [4]. Amongall the SLC transporters, SLCO gene subfamily that consists of theOrganicAnion Transporting Polypeptides (OATPs) as well as the SLC22A genesubfamily that encodes the Organic Anion Transporters (OATs) andOrganic Cation Transporters (OCTs/OCTNs), appear to be particularlyimportant in the cellular uptake of pharmaceutical agents [4–7]. Thesetwo subfamilies of SLCs are widely involved in the movement of alarge number of endogenous and exogenous substances across biologi-cal membranes. Their substrates are chemical divergent including cat-ions, anions as well as neutral and zwitterionic compounds [4]. Thedysfunction of SLCs not only disrupts homeostasis leading to diseases,but also largely impacts on the cellular uptake of drugs influencingtheir disposition in body [8]. Therefore, SLCs have been considered asthe key determinants to pharmacokinetic (PK) and pharmacodynamic(PD) profiles of various therapeutic drugs. Understanding the pharma-cological and physiological roles of SLCs greatly assists in diseaseprevention and drug treatments.

2. Organic Anion Transporting Polypeptides (OATPs)

OATPs are multispecific transporters with the broadest substratespectrum among all the SLC drug transporters [4]. Up to date, thereare 11 OATP isomembers identified in human,which are widely distrib-uted throughout human body, especially in the intestine, liver and kid-ney [9]. The substrates spectra of OATP isomembers are overlapping.The majority of OATP substrates are large hydrophobic anions. The pro-totypical endogenous substrates of OATPs include estrone-3-sulfate(ES), bile acids, thyroid hormones, prostaglandins, eicosanoids, steroidsand their conjugates; while the classic exogenous substrates of OATPsinclude anti-cancer agents like imatinib andmethotrexate, HIV proteaseinhibitors and statins [10–14]. OATP1A2, OATP1B1, OATP1B3 andOATP2B1 are the first few OATP isoforms cloned in human more than20 years ago, but they are recognised as the most important OATPsinvolved in drug pharmacokinetics [15].

In general, computer-based topological prediction suggested thatOATPs share a 12 transmembrane-domain structurewith a large 5th ex-tracellular loop. Additionally, it is conserved that OATPs have multiple

N-glycosylation sites in the extracellular loops 2 and 5 as well as the“signature” structure at the border between the extracellular loop 3and the transmembrane domain 6 [16] (Fig. 1). Hanggi et al. reportedthat mutations introduced to the cysteine residues located in the largeextracellular loop 5 of OATPs resulted in misfolded OATP proteinsready for degradation [17]. Altered post-translational modifications, inparticular N-glycosylation were shown to impact on OATP function[18,19]. Recently, it has been demonstrated by us and others that twoconserved tryptophan residues and two specific subregions of trans-membrane domain 6 are required for OATP-substrate binding, proteintrafficking and quality control [20,21]. Overall, the conserved topologi-cal structure of OATPs is essential inmaintaining their transport activity.

Genetic polymorphisms of SLCO genes have been widely reported ina number of populations [22]. Several genetic variants coded by SLCOpolymorphisms showed altered transporter function, which in turn,greatly impact on the pharmacokinetic performance of their drug sub-strates; therefore, it has emerged that the knowledge on SLCO geneticpolymorphisms should be implied in tailoring drug therapy in thefuture [22].

2.1. OATP1A2

OATP1A2 (encoded by the SLCO1A2 gene) is the first cloned humanOATP isoform, which protein is expressed in the renal tubular epitheli-um, brain capillary endothelium, biliary cholangiocytes and recentlyfound at the retinal pigment epithelium [23–26]. According to its tissuelocalisation, OATP1A2 regulates drug excretion into bile, secretion intourine and permeation at the blood–brain barrier; more interestingly, itis likely involved in the cellular uptake of all-trans-retinol into the reti-nal pigment epithelium as a part of the classic visual cycle to gain visionin human [23–26]. This transporter was also suggested to facilitate in-testinal drug absorption; however, more evidence is required to proveits expression in this tissue [27–29]. The prototypical drug substratesof OATP1A2 include imatinib, fexofenadine, methotrexate, HIV proteaseinhibitors and HMG-CoA reductase inhibitors [11,30–33].

Fig. 1. Putative topological model of OATPs. Transmembrane segments are numberedfrom 1 to 12. Potential glycosylation sites are denoted by “Y” shape.

22 F. Zhou et al. / Advanced Drug Delivery Reviews 116 (2017) 21–36

Genetic polymorphisms in OATP1A2 coding region and 5′ flankingregion have been indicated in the previous studies as well as the NCBIdbSNP database [14,26,32–36]. Non-synonymous polymorphisms withfunctional assessments are summarised in Table 1. Several genetic var-iants have been found to be dysfunctional in transporting OATP1A2classic substrates [14,26,32,33]. However, discrepancy was also noticedacross various studies. For instance, ES uptake mediated throughOATP1A2-I13T variant was shown to be unchanged in Xenopus laevisoocytes [33], but decreased in over-expressing HeLa cells [26]. Thismight be due to the different in vitromodels used in assessing the trans-port activity of this variant. According to the in vitro studies, OATP1A2genetic polymorphisms also potentially impact on the disposition andCNS entry of methotrexate [33] and opioid peptides, in particulardeltorphin II and [D-penicillamine2,5]-enkephalin [26].

Several pharmacogenomic studies invested the relationship ofOATP1A2 polymorphisms with imatinib pharmacokinetics, whichhave yielded inconsistent findings. The in vitro uptake of imatinib wasdecreased in cells containing the SLCO1A2*3 (516A→C), *5 (382A→T)and *6 (404A→T), but not *7 (2003C-NG) variant [32]. This study alsodemonstrated that the steady state plasma concentrations of imatinibwere not affected in patients carrying the *3 variant [32], whichsuggests that OATP1A2 polymorphisms not likely impact on imatinibpharmacokinetics. In contrast, an association was observed betweenpromoter region polymorphisms of SLCO1A2 (−1105G → A/−1032G→ A or−361GG) and imatinib clearance, although amechanismis not yet clear [35]. Considering drug response represents a complexphenotype encoded by a number of genes and affected by manyenvironmental factors, in vivo and clinical evidence will be required tofurther elucidate the involvement of OATP1A2 in the pharmacokineticsof imatinib and other pharmacological agents.

2.2. OATP1B1

OATP1B1 is primarily expressed at the sinusoidal membrane ofhuman hepatocytes, where it mediates the cellular uptake of amphi-philic organic compounds at a sodium- and ATP-independent manner.It can transport a broad spectrum of drugs such as statins, anti-viralsand endogenous substances like unconjugated bilirubin [31,37–39].Thus, SLCO1B1 polymorphisms are closely associated with serum biliru-bin level and people with specific SLCO1B1 polymorphisms are moresusceptible to hyperbilirubinaemia [37]. Several statins have beenfound to be transported through OATP1B1; therefore, this transporterplays an important role in the disposition of these statin substrates [40].

A large number of single nucleotide polymorphisms (SNPs) havebeen described in the SLCO1B1 gene and the OATP1B1 variants within vitro functional analysis are summarised in the Table 1. Generallyspeaking, a number of reported OATP1B1 variants have altered activityin transporting specific substrates,which suggests the genetic variationsof SLCO1B1 could have profound influence on the pharmacokinetics ofits drug substrates.

OATP1B1 haplotypes with specific polymorphisms in a single orcombination format have been extensively evaluated in in vitromodels,in particular OATP1B1*1b (N130D), *5 (V174A), *15 (N130D+ V174A)variants [41–48]. OATP1B1*1b variant is conserved for its transportfunction towards the uptake of ES, estradiol-17β-D-glucuronide (E2-17β-G) and several statins [42,45,46,48]; however, it is associatedwith an altered activity in transporting bromosulfophthalein (BSP)and cholyltaurine [45]. In contrast, OATP1B1*5-mediated uptake of ES,E2-17β-G, erythromycin, maraviroc and several statins are all signifi-cantly reduced, whichwas shown to be a consequence of the decreasedVmax and impaired cell surface expression of this variant transporterprotein [41,42,46,48]. As expected, the double variant OATP1B1*15 isalso associated with an impaired uptake of OATP1B1 drug substrates[41,42,48].

OATP1B1 is the OATP isoformwith themost pharmacogenomic dataavailable. It has been noticed that OATP1B1 interacted with several

statin drugs such as pravastatin [39,49], pitavastatin [50], rosuvastatin[51] and atorvastatin [42]. More importantly, in vitro and in vivo evi-dence indicated that OATP1B1 may play a major role in determiningthe hepatic uptake of statin drugs compared to other OATPs [50,52].For example, OATP1B1 521T → C polymorphism is shown to be relatedto the pharmacokinetics of atorvastatin in healthy Macedonian volun-teers [53]. OATP1B1 SNP 388A → G has been found to be associatedwith patient response to atorvastatin in a Chilean population [54]; how-ever, no impact on that of the Greek population [55]. Such contradictoryresultsmay be largely due to the small sample sizes included these stud-ies as well as different ethnical background of the cohorts. Additionally,Hubacek et al. reported that OATP1B1 high frequency non-coding poly-morphism (rs4363657) is not associatedwith statin-inducedmyopathyin a Czech population [56]; however, a genome-wide association studyindicated a single strong association of simvastatin-induced myopathywith this polymorphism [57]. As future studies arise, more clinicalevidence with large sample cohorts is highly desired to consolidatethese findings.

2.3. OATP1B3

OATP1B3, encoded by SLCO1B3 gene, is the other well-known liverspecific transporters that are localised at the basolateral membrane ofhepatocytes [15]. It can transport various substrates including front-line agents, paclitaxel [58] and diclofenac [59]. SLCO1B3 gene has alsobeen found to be polymorphic [34,36,60,61]; however, such informa-tion is relatively sparse compared to OATP1B1. As shown in Table 1,OATP1B3 variants coded by non-synonymous SNPs have been function-ally assessed [60,62] with several variants have altered uptake activitynot common to all but only to specific substrates. For instance,OATP1B3-S112A variant has increased uptake activity in transportingcholecystokinin (CCK-8), dehydroepiandrosterone-3-sulfate (DHEAS)and ES; while its function is reserved for BSP, E2-17β-G andcholyltaurine uptake [62]. Such functional modulation is possiblydue to their altered transporter-substrate binding affinity. Notewor-thy, in vitro findings about the uptake activities of OATP1B3 variantsis not necessarily consistent with other reports [60].

Compared to OATP1B1, less information is available regarding theinfluence of OATP1B3 variations on drug pharmacokinetics. Smithet al. showed that paclitaxel is a drug substrate of OATP1B3 [58], al-though its uptake may not be exclusive to this transporter protein[63]. The three common OATP1B3 SNPs 334T → G, 699G → A and1564G → T were investigated in 475 individuals with diverse ethnicbackground and 90 European Caucasian patients received paclitaxel;however, no direct association was found between these transporterSNPs and paclitaxel disposition [64].

2.4. OATP2B1

OATP2B1 is expressed abundantly at the basolateral mem-brane of hepatocytes as well as in several other tissues like thesyncytiotrophoblasts, intestine, keratinocytes, mammary gland, bloodbrain barrier and heart [65–68]. OATP2B1 was found to transport bileacid such as taurocholic acid [69] and several marketed drugs likeatorvastatin [68], pravastatin [69,70] and rosuvastatin [51].

Non-synonymous SNPs of OATP2B1 gene has been reported withonly the two variants T392I (encoded by 1175C → T) and S486F(encoded by 1457C → T) functionally characterised [46]. Imanagaet al. investigated the association of the genotype of SLCO2B11457C → T with drug performance, which study suggested that thepharmacokinetics of fexofenadine but not midazolam may be alteredin patients with this polymorphism [71]. However, due to the lack of in-formation regarding the activity of S486F in transporting fexofenadineandmidazolam, it is not clearwhether the observed fexofenadine phar-macokinetic change is indeed related to the phenotype of this variant.

23F. Zhou et al. / Advanced Drug Delivery Reviews 116 (2017) 21–36

Table 1Summary of genetic variants of OATPs with functional and/or expressional analysis.

Transporter Gene Geneticpolymorphism

Amino acidchange

Transport activity change Protein expression change transporter kineticCharacteristics

OATP1A2 (OATP-A) SLCO1A2 38T-NC I13T ES and MTX uptake ↑ [33]ES, Deltorphin II and DPDPE uptakeunchanged [26]Imatinib uptake unchanged [32]

Cell surface and total cellexpression unchanged [26]

Km of ES uptake unchanged[26,33]Vmax of ES uptake ↑ [33] orunchanged [26]Vmax of Deltorphin IIuptake unchanged [26]

382A-NT N128Y ES uptake unchanged [26,33]MTX uptake unchanged [33]Deltorphin II and DPDPE uptakeunchanged [26]Imatinib uptake ↓ [32]

Total cell expression ↓ [26] Vmax of Deltorphin IIuptake ↓ [26]

404A-NT N135I MTX uptake Unchanged [33]ES uptake unchanged [33] or ↓ [26]Deltorphin II and DPDPE uptake ↓ [26]Imatinib uptake ↓ [32]

Cell surface and total cellexpression ↓ [26]

Vmax of ES uptake ↓ [26]

502C-NT R168C MTX uptake ↓ [33]516A-NC E172D MTX uptake ↓ [33]

ES, Deltorphin II and DPDPE uptake ↓[26]Imatinib uptake ↓ [32]

Total cell expression ↓ [26] Km of MTX uptakeunchanged [33]Vmax of ES uptake ↓ [26,33]Vmax of MTX uptake ↓ [33]

550G-NA E184K ES, imatinib and MTX uptake ↓ [14] Cell surface and total cellexpression ↓[14]

553G-NA D185N ES, imatinib and MTX uptake ↓ [14] Cell surface and total cellexpression ↓[14]

559G-NA A187Y ES uptake ↓ [26]Deltorphin II and DPDPE uptakeunchanged [26]

Vmax of ES uptake ↓ [26]Vmax of Deltorphin IIuptake unchanged [26]

763G-NA V255I ES, imatinib and MTX uptakeunchanged [14]

Cell surface expression unchanged[14]

775A-NC T259P ES, imatinib and MTX uptake ↓ [14] Cell surface and total cellexpression ↓[14]

833A-Ndel N278DEL Nonfunctional [33]862G-NA D288N ES, imatinib and MTX uptake ↓ [14] Cell surface expression ↓[14]

Total cell expression unchanged[14]

2003C-NG T668S ES, Deltorphin II and DPDPE uptakeunchanged [26]Imatinib uptake ↓ [32]

Cell surface and total cellexpression ↓ [26]

Km of ES uptake unchanged[33]Vmax of ES uptakeunchanged [33]

OATP1B1 (OATP2,OATP-C and LST-1)

SLCO1B1 217T-NC F73L ES and E2-17β-G uptake ↓ [48] Cell surface and total cellexpression ↓[48]

Km of ES uptake ↑ [48]

245T-NC V82A ES and E2-17β-G uptake ↓ [48] a Cell surface expression ↓[48]aTotal cell expression unchanged[48]a

Km of ES uptake ↑ [48] *

388A-NG N130D ES and E2-17β-G uptake unchanged[42,45,48]Pravastatin, atorvastatin andcerivastatin uptake unchanged [46]BSP uptake ↑ [45][45] uptake ↓ [45]


Km and Vmax of ES uptakeunchanged [46]

452A-NG N151S ES and E2-17β-G uptake unchanged [48]455G-NA R152K E2-17β-G uptake↓ [48]a463C-NA P155T ES and E2-17β-G uptake unchanged [48]

BSP, E2-17β-G and cholyltaurineuptake ↓ [45]

Total cell expression ↓ [45]

467A-NG E156G ES and E2-17β-G uptake ↓ [48] a Cell surface expression ↓[48]aTotal cell expression unchanged[48]a

Km of ES uptake ↑ [48] *

521T-NC V174A ES and E2-17β-G uptake ↓[41,42,44,48]Erythromycin uptake ↓ [44]Maraviroc uptake ↓ [47]Pravastatin, atrasentan atorvastatinand cerivastatin uptake ↓ [42,43]

Cell surface expression ↓[48]Total cell expression unchanged[41,48]

Vmax of ES uptake ↓ [48]Km and Vmax of ES uptakeunchanged [46]Vmax of pravastatin andatorvastatin uptake ↓ [42]

578T-NG L193R ES and E2-17β-G uptake unchanged [48]No BSP, E2-17β-G and cholyltaurineuptake [45]


721G-NA D241N E2-17β-G uptake↓ [48]b1007C-NG P336R ES and E2-17β-G uptake unchanged

[48]ES uptake ↑ and E2-17β-G uptake ↓[41,42]pravastatin, atorvastatin andcerivastatin uptake unchanged [42]


In addition, contradictory findings were noticed in the case ofmontelukast. In 2009, the study of Mougey et al. revealed thatSLCO2B1 935G → A polymorphism (rs12422149) is associated with asignificantly reduced plasma concentration of montelukast in patients[72]; furthermore, the follow-up study of this group rectified that peo-ple with this polymorphism is more susceptible to the impact of citrusjuice (OATP2B1 inhibitor) on montelukast disposition [73]. However,the other two later studies showed that SLCO2B1 polymorphisms playa minor role in determining montelukast pharmacokinetics [74,75].Thus, in vitro functional evaluation of the relevant OATP2B1 variantsin respect to montelukast transport is highly desired to appropriatelyinterpret the clinical observations.

2.5. Other OATPs

OATP1C1 (OATP-F) is a high affinity thyroid transporter expressed inthe blood–brain barrier, placenta, testis and ciliary body [76–78].

OATP1C1 3035C → T polymorphism was found to be associated withfatigue and depression in hypothyroid patients [79]; however, thetransport function of OATP1C1 genetic variants in uptaking thyroidswas not altered [80]. Further investigation is expected to establish themolecular basis of the association between OATP1C1 3035C → Tpolymorphism and the diseases mentioned above.

OATP2A1 (also known as human PGT) is a specific prostaglandintransporter with broad tissue localisation [81]. It is postulated that thepolymorphisms of OATP2A1 are associated with cancer development[82] and primary hypertrophic osteoarthropathy [83–86]. However, lit-tle is available about the functional consequence of the identifiedOATP2A1 polymorphisms.

OATP3A1 (OATP-D) exists as two splice variants with the short var-iant has a limited tissue localisation to the brain and testis; while thelonger variant is widely expressed through many tissues [87]. It cantransport a number of hormones including thyroxin, ES, prostaglandinE1 (PGE1) and prostaglandin E2 (PGE2) [87,88]. Literature indicated

Table 1 (continued)


Amino acidchange

Transport activity change Protein expression change transporter kineticCharacteristics

1058T-NC I353T ES and E2-17β-G uptake ↓ [48] Cell surface expression ↓[48]Total cell expression unchanged[48]


1294A-NG N432D E2-17β-G uptake ↓ [48] Vmax of ES uptake ↓ [48]1385A-NG D462G ES and E2-17β-G uptake unchanged [48]1454G-NT C485F ES and E2-17β-G uptake unchanged [48]1463G-NC G488A ES, atrasentan and E2-17β-G uptake ↓

[43,48]Cell surface expression ↓[48]Total cell expression unchanged[48]

Vmax of ES uptake ↓ [48]

1964A-NG D655G ES uptake ↓ [48]E2-17β-G uptake unchanged [48]


2000A-NG E667G ES and E2-17β-G uptake unchanged [48]OATP1B3 (OATP8) SLCO1B3 334T-NG S112A BSP, E2-17β-G, C-tau uptake

unchanged [62]CCK-8, DHEAS and ES uptake ↑ [62]CCK-8 uptake unchanged [60]

Membrane expression unchanged[62]Total cell expression ↑ [60]Cell surface expression unchanged[60]

Km of BSP uptake ↑ [62]Vmax of BSP uptake ↑ [62]Km and Vmax of CCK8uptake unchanged [60]

439A-NG T147A CCK-8 uptake unchanged [60] Total cell expression ↑ [60]Cell surface expression unchanged[60]

699G-NA M233I BSP, CCK8, E2-17β-G, DHEAS, C-tauuptake unchanged [62]ES uptake ↑ [62]CCK-8 and rosuvastatin uptake ↓ [60]Atorvastatin uptake unchanged [60]

Membrane expression unchanged[62]Total cell and cell surfaceexpression unchanged [60]

Km of BSP uptake ↑ [62]Vmax of BSP uptake ↑ [62]Km unchanged and Vmax ↓of CCK8 uptake [60]

767G-NC G256A CCK-8 uptake unchanged [60] Total cell expression ↓ [60]Cell surface expression unchanged[60]

1559A-NC H520P CCK-8 and rosuvastatin uptake ↓ [60]Atorvastatin uptake unchanged [60]

Total cell and cell surfaceexpression ↓ [60]

Km unchanged and Vmax ↓of CCK8 uptake [60]

1564G-NT G522C BSP, CCK8, DHEAS, C-tau uptake ↓ [62]E2-17β-G uptake unchanged [62]ES uptake ↑ [62]

Membrane expression ↓ at thehighly glycosylated form butunchanged at the lower molecularweight form [62]

Km of BSP uptakeunchanged [62]Vmax of BSP uptake ↓ [62]

1679T-NC V560A CCK-8 and rosuvastatin uptake ↓ [60]Atorvastatin uptake unchanged [60]

Total cell and cell surfaceexpression ↓ [60]

Km unchanged and Vmax ↓of CCK8 uptake [60]

1748G-NA G583E BSP, CCK8, DHEAS, C-tau uptake ↓ [62]E2-17β-G uptake unchanged [62]ES uptake ↑ [62]

Membrane expression ↓ at thehighly glycosylated form butunchanged at the lower molecularweight form [62]

Km of BSP uptakeunchanged [62]Vmax of BSP uptake ↓ [62]

OATP2B1 (OATP-B) SLCO2B1 1175C-NT T392I ES uptake moderately reduced [46] Cell surface expression ↑ [46] Km and Vmax of ES uptakeunchanged [46]

1457C-NT S486F ES uptake ↓ [46] Cell surface expression ↑ [46] Km and Vmax of ES uptakeunchanged [46]

OATP1C1 (OATP1,OATP-F, OATPRP5,OATP14)

SLCO1C1 427C-NA P143T T4 uptake unchanged [80]

OATP5A1 (OATP-J) SLCO5A1 L33F Protein expression unchanged[106]

ES: Estrone-3-sulfate; MTX: Methotrexate; DPDPE: [D-penicillamine2,5]-enkephalin; E2-17β-G: estradiol-17β-D-glucuronide; BSP: bromosulfophthalein; CCK8: cholecystokinin; DHEAS:dehydroepiandrosterone-3-sulfate; C-tau: cholyltaurine; T4: thyroxine.

a The haplotype tested with both T245C and A467G polymorphisms.b The haplotype tested with both G721A and G455A polymorphisms.


the differential expression of OATP3A1 in various tumour cellscompared to non-tumour cells, suggesting the role of this transporterin hormone-dependent tumour progression [89–95].

OATP4A1 (OATP-E) is expressed in multiple organs such as thebrain, mammary gland and fetal cerebral cortex [77,96,97]. It is knownto transport thyroid hormones and ES [65,98].

OATP4C1 (OATP-H) is a renal transporter protein that is responsiblefor the uptake of cardiac glycosides like digoxin and ouabain, thyroidhormones, ES, methotrexate, sitagliptin and uremic toxins [99–102]. In-terestingly, the genetic variation of OATP4C1was found to be associatedwith preeclampsia [103].

OATP5A1 (OATP-J) distributes at the lung, brain, heart and breast tis-sue [90,104,105]. Noteworthy, it does not transport the common OATPsubstrates and has no known substrate currently. Further studies willbe required to explore the function of this transporter [106]. A geneticvariant of OATP5A1 (L33F) has been identified with no expressionaland functional alternation.

OATP6A1 (OATP-I) expressionwas identified in the testis, lung aswellas a few other tissues [104,107,108] with little known about its function.

So far, there is no information available regarding the genetic poly-morphisms of OATP3A1, OATP4A1 and OATP6A1.

3. Organic anion transporters (OATs)

Organic anion transporters are one of the important SLC subfamiliesthat encoded by SLC22A genes. Up to date, there are 11OAT isomembershave been identified inmammalian species. Among all the humanOATs,OAT1-4 are the best characterised isomembers. Generally speaking,OATs are responsible for the uptake of a broad spectrum of substancesincluding anti-cancer drugs, antibiotics, anti-hypertensives. Most OATsare localised in the human kidney and/or liver with the exemption ofOAT6 expressing at the nasal epithelium [7,109,110].

OAT1, OAT2 and OAT3 distributes at the basolateral membrane ofrenal proximal tubular cells and responsible for moving drugs/toxinsinto the kidney for subsequent elimination into the urine [111–116].In contrast, OAT4, OAT10 and URAT1 are found at the apical membraneof the renal proximal tubule in charge of the reabsorption of substancesfrom the urine [117–119]. OAT2, OAT7 and OAT9 are expressed at thesinusoidal membrane of hepatocytes [114,118,120–123].

In the kidney, OATs follow a tertiary transport mode that coupledwith the Na+ K+-ATPase and sodium dicarboxylate cotransporter. Aninwardly directed sodium gradient sustained by the function ofNa+K+-ATPase drives the moving of dicarboxylate into the cells,which consequently maintain an outwardly dicarboxylate gradientthat utilised by OATs to exchange their substrates into the cells. Thisprocess consumes energy to allow the cellular entry of anionicsubstances against their chemical concentrations and the electricalpotential of cells [112,117,124–126].

Similar to OATPs, computermodeling predicted that OATs also sharecommon structural features including 12 putative transmembrane do-mains, intracellular carboxyl- and amino-termini, as well as the largeextracellular loop between the transmembrane domain 1 and 2 withmultiple N-glycosylation sites [127,128] (Fig. 2).

3.1. OAT1

OAT1was thefirstmembrane cloned of theOAT subfamily in human[111,112]. Human OAT1 was reported to have four splice variants pres-ent in the kidneywith the two functional variants (OAT1-1 andOAT1-2)and the other two dysfunctional variants (OAT1-3 and OAT1-4) [116,125,129,130]. OAT1 can transport a range of substances includingnucleoside phosphate antibiotics [131] and anti-cancer agents likemethotrexate [132], among which p-Aminohippurate (PAH) has longbeen considered as the prototypical substrate of OAT1 [125,129].

Genetic polymorphisms of OAT1 have been reported in variousstudies [133–136]; however, information regarding the functional

characterisation of these variants was not much. As shown in theTable 2, Bleasby et al. showed that the Km of OAT1-R50H variant inuptaking cideofovir, adefovir and tenofovirwere significantly increased;while their Vmax values were reduced [133]. OAT1-K525I variantdiscussed in the same study has reserved transport activity comparedto the wild type [133]. Xu et al. demonstrated that nonsynonymouspolymorphisms of OAT1 might not be frequent; therefore, it is impor-tant to consider the influence of the polymorphisms from the promoterregion that may regulate the expression of OAT1 [134]. The gene associ-ation study conducted by Han et al. indicated that the intergentic poly-morphism of OAT1 and OAT3 (rs10792367) may be correlated withinter-patient variation towards hydrochlorothiazide [136]. Due to theessential role of OAT1 played in the renal elimination of drugs andtheirmetabolites aswell as various toxins, it is important that functionalassessment of OAT1 variants in vitro can also be available to facilitate theinterpretation of clinical and in vivo observations.

3.2. OAT2

OAT2 is abundantly expressed in the liver and to a less extent in thekidney [110,121,137]. It transports a variety of organic anions includingPGE2, α-ketoglutarate (α-KG), cAMP, methotrexate, glutarate and PAH[110,121,137–139].

OAT2 polymorphisms have been identified in the coding region[134]; however, functional analysiswith these variants has not been per-formed yet. The study of Ogasawara et al. investigated the regulatorypolymorphisms of OATs [140]; however, regulatory SNP was found inneither the OAT1 nor the OAT2 gene. In addition, eight synonymousSNPs of OAT2 were reported in a Korean population with no correlationto the variable protein expression of OAT2 in these human subjects [135].

3.3. OAT3

OAT3, encoded by SLC22A8 gene,was cloned from the human kidney[113,116] with less abundant mRNA expression in the adrenal tissue[141]. Although it localised at the basolateral membrane of the renalproximal tubule together with OAT1, the substrate selectivity of OAT3is somewhat different from that of OAT1. For instance, the Km valuesof PAH for OAT1 and OAT3 are nearly 10 folds different (9 μM and87 μM, respectively) [113] and OAT3 contributes to the renal uptake ofrosuvastatin; while OAT1 does not interact with this drug [142].

Fig. 2. Putative topological model of OATs and OCTs. Transmembrane segments arenumbered from 1 to 12. Potential glycosylation sites are denoted by “Y” shape.


Noteworthy, the substrate selectivity of OAT3 is not as rigid as OAT1,since it can transport cationic drugs like cimetidine [143].

Several reports have identified the genetic variations of SLC22A8 gene[144,145], with the study of Erdman et al. extensively characterisedten OAT3 variants regarding their function and transporter kinetics(Table 2) [143]. Noteworthy, OAT3-I305F is a common variant, which

has been found to be associated with the reduced cefotaxime clearancein patients [144]. In contrast, there was no correlation found betweenOAT3 variants and the PK profiles of drugs like torsemide [146] andpravastatin [145]. Additionally, regulatory polymorphisms of OAT3were investigated, which were not shown to be critical in modulatingthe mRNA expression of this transporter [140].

Table 2Summary of genetic variants of OATs with functional and/or expressional analysis.


Amino acidchange

Transport activity change Protein expression change Transporter kinetic characteristics

OAT1 (PAHT) SLC22A6 149G-NA R50H PAH uptake unchanged[133]

Km and Vmax of PAH uptake unchanged [133]Km of adefovir, cidofovir and tenofovir uptake ↓[133]Vmax of adefovir, cidofovir and tenofovir uptake↓ [133]

1574A-NT K525I PAH uptake unchanged[133]

Km of PAH, adefovir, cidofovir and tenofoviruptake unchanged [133]

OAT3 SLC22A8 387C-NA F129 L ES and CIM uptakeunchanged [143]

445C-NA R149S ES and CIM uptake ↓ [143]715C-NT Q239Stop ES and CIM uptake ↓ [143]779T-NG I260R ES and CIM uptake ↓ [143]829C-NT R277W ES uptake ↓ [143]

CIM uptake moderately ↓[143]

842T-NC V281A ES and CIM uptakeunchanged [143]

913A-NT I305F ES uptake ↓ [143]CIM uptake unchanged[143]

Total cell expressionunchanged [143]

Km and Vmax of ES and CIM uptake unchanged[143]Km of cefotaxime uptake unchanged [144]Vmax of cefotaxime uptake ↓ [144]

929C-NT A310V ES and CIM uptakeunchanged [143]

1195G-NT A399S ES and CIM uptakeunchanged [143]

1342G-NA V448I ES and CIM uptakeunchanged [143]

Km of ES and CIM uptake ↓ [143]Vmax of ES of CIM uptake unchanged [143]

OAT4 (hOAT4) SLC22A11 37G-NA V13M ES uptake unchanged [152]L29P ES uptake ↓ [152] Total cell and surface

expression ↓ [152]I31V ES uptake unchanged [152]

142C-NT R48Y ES uptake ↓ [152] Total cell and surfaceexpression ↓ [152]

185T-NG T62R ES uptake unchanged [152]V155G ES uptake ↓ [152] Total cell and surface

expression ↓ [152]Vmax of ES uptake ↓ [152]Km of ES uptake ↑ [152]

463G-NA V155M ES uptake unchanged [152]732C-NT A244V ES uptake unchanged [152]1015G-NA T339M ES uptake unchanged [152]1175C-NT T392I ES uptake ↓ [152] Total cell and surface

expression ↓[152]Vmax of ES uptake ↓ [152]Km of ES uptake unchanged [152]

URAT1 (OAT4L, RST) SLC22A12 193G-NT G65W Urate uptake ↓ [159]269G-NA R90H Urate uptake ↓ [164] Cell surface expression

unchanged [164]412G-NA V138M Urate uptake ↓ [164] Cell surface expression

unchanged [164]490G-NA G164S Urate uptake ↓ [164] Cell surface expression

unchanged [164]650C-NT T217M Urate uptake ↓ [119] Total cell expression

unchanged [119]774G-NA W258Stop Urate uptake ↓ [165] Total cell expression ↓ [119]894G-NT E298D Urate uptake ↓ [119] Total cell expression

unchanged [119]1145A-NT Q382L Urate uptake ↓ [164] Cell surface expression

unchanged [164]1289T-NC M430T Urate uptake ↓ [164] Cell surface expression ↓[164]1639-1643del 547Frame

shiftUrate uptake ↓ [164] Cell surface expression ↓[164]

OAT7 SLC22A9 268C-NT R90C ES and pravastatin uptake ↓[171]


1298C-NT T433M ES and pravastatin uptake ↑[171]


1437A-NG I479M ES and pravastatin uptake ↑[171]


Note: PAH: p-Aminohippurate; CIM: cimetidine; ES: estrone-3-sulfate.


3.4. OAT4

OAT4 is distinct from OAT1-3, which is expressed at the apical(urine-facing) membrane of the renal proximal tubular cells as well asat the basal side of the syncytiotrophoblasts. Due to its tissuelocalisation, it is involved in the reabsorption of organic anions fromurine, elimination of molecules into the urine and uptake of steroid pre-cursors from fetal blood [147,148]. Similar to OAT3, ES is the classic sub-strate of OAT4. It can also transport the other sulfate steroid like DHEASand the purine metabolite urate [147,149]. Other drug substrates ofOAT4 reported include tetracycline [150] and methotrexate [151].

Eight nonsynonymous SNPs were reported in 2005 [134] and later,we provided evidence in the molecular characterisation of these vari-ants [152]. It showed that OAT4-L29P, −R48Y, −V155G and –T392Ihave reduced transport activity (Table 2), which are partially due tothe impaired protein expression of these variant transporters. Literaturealso demonstrated that OAT4genetic polymorphismsmay be associatedwith the altered renal clearance of torsemide and renal underexcretiontype gout [146,153,154]. However, the molecular findings on OAT4genotypes cannot readily be used to interpret the in vivo observations.

3.5. URAT1

URAT1was originally considered as a renal specific transporter [119];later, it was also detected at vascular smoothmuscles [155]. In the kidney,it is expressed at the apical (urine-facing) membrane, where it is respon-sible for the reabsorption of urate into the proximal tubules coupledwiththe exchange of intracellular lactate [119]. URAT1 has a low affinity tourate [119]; however, its affinity to the pyrimidine precursor orotate isrelatively high [156].

Literature has reported genetic mutations in URAT1 gene since 2002,with several studies identified the association of URAT1 polymorphismswith renal hyperuricemia, mainly in Asian populations [119,153,157–163]. All the genetic variants of URAT1 functionally characterised showreduced transport activity [119,159,164,165], which revealed a highrisk of renal hypouricaemia in people with genetic deficiency of URAT1.Additionally, URAT1 polymorphismsmight be associatedwithmetabolicsyndrome and obesity [166] as well as influence on the uricosuric actionof losartan in hypertensive patients with hyperuricemia [167].

3.6. Other OATs

OAT5 is a liver specific transporter with little information availableon its function and physiological role [110,168]. OAT6 is identified atthe nasal epithelium [169], where it may contribute to remote senseof odorants. Zimmerman et al. indicated that OAT6mediates the uptakeof anti-cancer agent sorafenib in human epidermal keratinocytes [170],which may be involved in the skin toxicity of this agent. OAT7 is a liverspecific transporter expressed at the sinusoidal membrane of hepato-cytes, where it exchange sulfate steroids for butyrate [123]. The recentstudy indicated that OAT7 plays a role in the hepatic uptake of prava-statin; the inter-individual variability of this transporter may be dueto the regulatory effect of Hepatic nuclear factor 4-alpha [171]. Thesame study also identified several genetic variants of OAT7 in a cohortof 126 Caucasian subjects, three of which (R90H, T433M and I479M)have reduced protein expression and altered transport function(Table 2) [171]. Oat8 and Oat9 were cloned from rodents [172,173];however, their human orthologues have not been discovered. HumanOAT10, previously known as “organic cation transporter like 3”(ORCTL3) is abundant in the kidney and weakly expressed in severalother tissues including the brain and intestine [118,174]. Nicotinateand urate have been reported as the substrates of OAT10 [118]. Uponfrom what mentioned above, little is known about the polymorphismsof these OAT isomembers.

4. Organic cation transporters (OCTs/OCTNs)

SLC22A genes also encode three subtypes of organic cation trans-porters: the electrogenic organic cation transporters (OCT1, OCT2and OCT3) that are sodium- and proton-independent; electroneutralorganic cation transporters (OCTN1, OCTN2 and OCTN3) as well as thecarnitine/cation transporter OCT6. These transporters mainly mediatethe transport of organic cations that are positively charged at physiolog-ical pH, in or out of cells. They are defined as “polyspecific”, sincethey mediate the transport of diverse substrates with different molecu-lar structures and sizes [175]. They are primarily distributed in thekidney, liver and intestine, where they play a vital role in drugdisposition [175].

Similar to OATs and OATPs, it was also predicted that OCTs/OCTNsshare common topological structures containing 12 transmembrane do-mains, an intracellular N- and C-terminus as well as a large extracellularloop between transmembrane domains 1 and 2 [175]. There are a fewsubstrates that are common to OCT1, OCT2 and OCT3, which include1-methyl-4-phenylpyridinium (MPP+) and tetraethylammonium(TEA) [175,176].

4.1. OCT1

Human OCT1 and OCT2 were identified by Gorboulev et al. in 1997through homology screening [177]. OCT1 was first found to beexpressed in the liver, where it is involved with hepatic excretion oforganic cationic molecules. Later, it was also detected at the luminalmembrane of the bronchial epithelial cells [178] and in the placenta[179], where it partially mediates the release of acetylcholine. It cantransport the common substrates of OCTs as well as drugs likemetformin [180].

A number of studies have revealed that OCT1 genetic variations arepotentially associated with the pharmacokinetic performance of met-formin in type 2 diabetes patients, which information has been wellsummarised in the previous good reviews [181,182] and will not be re-peated in this review. Besides that, OCT1 genotypes have been shown toimpact on thedisposition of several other drugs such asmorphine. Stud-ies showed that in children, OCT1 genotypes largely determine thepharmacokinetics of intravenously injected morphine, in particular de-fective OCT1 variants potentially lead to a reduced clearance of mor-phine and consequently a higher frequency of toxicity [183–185].Functional characterisation revealed that several OCT1 variants (R61C,Q97K, C88R, P117L, R206C, G220V, P283L, P341L, G401S, G410S andG465R) were shown to have altered transport activity to specific sub-strates [180,186–189], which indicated the different roles of theseamino acids in determining transporter-substrate binding and proteinexpression (Table 3).

4.2. OCT2

OCT2 has been identified in multiple human tissues especially thekidney and brain [115,190]. It is expressed across various regions ofthe human brain, where it mediates the transport of dopamine, seroto-nin, histamine and other neurotransmitters; thus, it is plausible that theimpaired activity of OCT2 contributes to neurological dysfunctions inhuman [190]. Togetherwith OCT1, OCT2 is also shown to be responsiblefor the luminal release of acetylcholine from bronchial epithelial cells[178]. Noteworthy, Urakami et al. identified a splice variant of OCT2(OCT2-A) in human, which shares 81% similarity to the proteinsequence of OCT2 reference protein and has a narrower spectrum ofsubstrates compared to the reference transporter [191].

In exploring the interactions of OCT1 and OCT2 with n-tetraalkylammonium compounds and biguanides, Dresser et al.suggested that smaller hydrophilic substrates are more preferable to betransported by OCT2; while OCT1 favourably binds to larger, hydropho-bic substances in the liver [192]. Besides the common characteristics of


Table 3Summary of genetic variants of OCTs with functional and/or expressional analysis.


Amino acidchange

Transport activity change Protein expressionchange

Transporter kinetic characteristics

OCT1 SLC22A1 41CC-NT S14F MPP+ uptake ↑ [189] Km of MPP+ uptake ↓ [189]Vmax of MPP+ uptake ↑ [189]

181C-NT R61C MPP+ and sumatriptan uptake↓ [187–189] Km of MPP+ uptake ↑ [189]Vmax of MPP+ uptake ↓ [189]

L85F MPP+ uptake unchanged [189]292T-NC C88R MPP+, serotonin, sumatriptan and TEA

uptake↓ [187,188]289C-NA Q97K Metformin uptake ↓ [186] Total and cell surface

expressionunchanged [186]

Km of metformin uptake ↑ [186]Vmax of metformin uptake unchanged[186]

350C-NT P117L Metformin uptake ↓ [186] Total and cell surfaceexpressionunchanged [186]

Km of metformin uptake unchanged [186]Vmax of metformin uptake ↓ [186]

480C-NG G160L MPP+ uptake unchanged [187,189]566C-NT S189L MPP+ uptake unchanged [189]616C-NT R206C Metformin uptake ↓ [186] Cell surface

expression ↓ [186]Km of metformin uptake unchanged [186]Vmax of metformin uptake ↓ [186]

659G-NT G220V MPP+ uptake ↓ [189]848C-NT P283L Lamivudine, MPP+ and TEA uptake ↓ [180]

Metformin uptake unchanged [180]Km of lamivudine uptake unchanged [180]Vmax of lamivudine uptake ↓ [180]

1022C-NT P341L MPP+ uptake ↓ [189]TEA and lamivudine uptake ↓ [180]MPP+ and metformin uptake unchanged[180]

Km of MPP+ uptake ↑ [189]TEA and lamivudine uptake Vmax ofMPP+ uptake ↓ [189]Km of lamivudine uptake unchanged [180]

1025G-NT R342H MPP+ uptake unchanged [189]1201G-NA G401S MPP+, serotonin and TEA uptake ↓ [187,189]1222A-NG M408V MPP+ uptake unchanged [189]

G410S Sumatriptan uptake ↓ [180]1256delATG M420Del MPP+ and sumatriptan uptake unchanged

[187–189]1320G-NA M440I MPP+ uptake unchanged [189]1381G-NA V461I MPP+ uptake unchanged [189]1393G-NA G465R MPP+ and sumatriptan uptake ↓ [188,189] Cell surface

expression ↓ [189]1463G-NT R488M MPP+ uptake unchanged [189] Cell surface


OCT2 SLC22A2 495G-NA M165I MPP+ uptake ↓ [228] Km of MPP+ uptake unchanged [228]596C-NG T199I Sumatriptan, MPP+, TEA and metformin

uptake ↓ [180,229]Km of lamivudine uptake unchanged [180]Km of MPP+ uptake ↑ [229]Vmax of lamivudine and MPP+ uptake ↓[180,229]

602C-NT T201M Sumatriptan, MPP+, TEA and metforminuptake ↓ [180,229]

Km of lamivudine uptake unchanged [180]Km of MPP+ uptake ↑ [229]Vmax of lamivudine and MPP+ uptake ↓[180,229]

808G-NT A270S Sumatriptan, MPP+, dopamine,norepinephrine, and propranolol, TEA andmetformin uptake ↓ [180,229,230]MPP+ uptake unchanged [228]

Km of lamivudine and MPP+ uptakeunchanged [180] [228,230]Km of MPP+ and dopamine uptake ↑[229,230]Vmax of lamivudine, dopamine,norepinephrine, and propranolol andMPP+ uptake ↓ [180,229,230]

1198C-NT R400C MPP+ uptake ↓ [228] Km of MPP+ uptake unchanged [228]1294A-NC K432Q MPP+ uptake unchanged [228] Km of MPP+ uptake ↓ [228]

OCT3 (EMT,EMTH)

SLC22A3 A116S MPP+ and histamine uptake ↓ [203]

T400I MPP+ and histamine uptake ↓ [203]A439V MPP+ and histamine uptake ↓ [203]

OCTN1 SLC22A4 188G-NA R63H L-ergothioneine uptake ↓ [214] Total cell and surfaceexpression ↓ [214]

Km of L-ergothioneine uptake ↑ [214]Vmax of of L-ergothioneine uptake ↓ [214]

248G-NC R83P L-ergothioneine uptake ↓ [214] Total cell and surfaceexpression ↓ [214]

400C-NA L134M L-ergothioneine uptake unchanged [214]475G-NA V159M TEA and betaine uptake unchanged [212]494A-NG D165G TEA and betaine uptake ↓ [212] Cell surface

expression ↓ [212]Total cell expressionunchanged [212]

615G-NA M205I TEA and betaine uptake ↓ [212] Cell surfaceexpression ↓ [212]Total cell expressionunchanged [212]

(continued on next page)


OCTs, OCT2 has been shown to transport substrates in a bi-directionalmanner [178,190], which indicates its role in either influx or efflux ofsubstances across the cell membrane.

Several genetic variations have been identified for OCT2, most ofwhich are with reduced transport activity in the uptake of MPP+ andTEA (Table 3). It has been noticed that OCT2 genotypes contribute tometformin pharmacokinetics [181,182] as well as to the intern-patientvariation of other drug therapies. In 2009, Filipski et al. indicated thatOCT2-A270S variant was associated with reduced cisplatin-inducednephrotoxicity [193], which was also confirmed by Lanvers-Kaminskyet al. [194]. Iwata et al. demonstrated that this effect is not due to its in-fluence on cisplatin disposition [195].

4.3. OCT3

Different from OCT1 and OCT2, OCT3 showed a broad distributionpattern across various tissues with the highest expression in skeletalmuscle, liver, placenta and heart [196–200]. It was first cloned as thecorticosterone-sensitive extraneuronal catecholamine transporter.With its wide distribution in human body, it is plausible that thistransporter captures the excessive monoamine transmitters escapedfrom neuronal re-uptake, which then avoid the uncontrolled spreadingof signals [199].

In contrast to OCT1 and OCT2, OCT3 is able to transport cationic sub-stances such as MPP+ and non-charged compounds like histamine

Table 3 (continued)


Amino acidchange

Transport activity change Protein expressionchange

Transporter kinetic characteristics

774G-NC M258I L-ergothioneine uptake unchanged [214]844C-NT K282Stop TEA and betaine uptake ↓ [212]917C-NT T306I TEA and betaine uptake unchanged [210,212] Total cell and surface


Km and Vmax of TEA uptake unchanged[210]

1031T-NA M344K L-ergothioneine uptake unchanged [214]1445G-NA G482D L-ergothioneine uptake ↓ [214] Total cell and surface


Km of L-ergothioneine uptake unchanged[214]Vmax of of L-ergothioneine uptake ↓ [214]

1460T-NC M487T L-ergothioneine uptake unchanged [214]1499T-NA I500N L-ergothioneine uptake ↓ [214] Total cell and surface

expression ↓ [214]Km of L-ergothioneine uptake ↓ [214]Vmax of L-ergothioneine uptake ↓ [214]

1531G-NA G462E TEA uptake ↓ [210] Total cell expressionunchanged [210]

1507C-NT L503F TEA uptake ↑ [212]Betaine uptake unchanged [212]Gabapentin uptake ↓ [211]

Total cell and surfaceexpressionunchanged [212]

Km of TEA uptake ↓ [212]Vmax of TEA uptake ↑ [212]Km and Vmax of betaine uptakeunchanged [212]

OCTN2 (CDSP) SLC22A5 51C-NG F17L L-carnitine and TEA uptake ↓ [217,219] Km of L-carnitine uptake unchanged [219]Km of TEA uptake ↑ [219]Vmax of TEA and L-carnitine uptakeunchanged [219]

325G-NC E109Q L-carnitine and TEA uptake unchanged [218]364G-NT D122Y L-carnitine and TEA uptake ↓ [218] Cell surface


430C-NT L144F L-carnitine and TEA uptake unchanged[217,219]

Km and Vmax of TEA and L-carnitineuptake unchanged [219]

523G-NA V175M L-carnitine and TEA uptake unchanged [218]573G-NT K191N L-carnitine and TEA uptake unchanged [218]614C-NT A214V L-carnitine and TEA uptake unchanged [218]791C-NT T264M L-carnitine uptake ↓ [217]904A-NG K302E L-carnitine and TEA uptake ↓ [218] Cell surface


Km of L-carnitine uptake unchanged [218]Vmax of L-carnitine uptake ↓ [218]

934A-NG I312V L-carnitine uptake unchanged [217]949G-NA E317K L-carnitine uptake ↑ [217]

M352R L-carnitine uptake ↓ [215] Total cell expressionunchanged [215]

1345T-NG Y449D L-carnitine uptake ↓ [217,219]TEA uptake unchanged [219]

P478L L-carnitine uptake ↓ [215] Total cell expressionunchanged [215]

1441G-NT V481F L-carnitine and TEA uptake ↓ [219]V481I L-carnitine uptake unchanged [217]

1463G-NA R488H L-carnitine uptake unchanged [217]1522T-NC F508L L-carnitine and TEA uptake unchanged

[217,219]1588A-NG M530V L-carnitine and TEA uptake unchanged

[217,219]1645C-NT P549S L-carnitine and TEA uptake unchanged

[217,219]Km and Vmax of TEA and L-carnitineuptake unchanged [219]

MPP+: 1-methyl-4-phenylpyridinium; TEA: tetraethylammonium.


[201], which demonstrates the functional discrimination of OCT3compared to the other two OCTs. Due to the wide expression of OCT3in peripheral tissues, it has been shown to play a role in the distributionand elimination of metformin in these tissues [202].

Our knowledge on OCT3 polymorphism is limited (Table 3). Sakataet al. functionally characterised the genetic variants of OCT3, whichstudy found OCT3-A116S, -T400I, and -A439V variants have impairedtransport activity as to the uptake of MPP+ and histamine [203]. Thissuggested an inter-individual variation of cationic drug disposition inpeople with such polymorphisms. This also indicated a higher suscepti-bility of hypertension, allergic diseases and neuropsychiatric diseases inthese people due to the dysfunction of OCT3 in the clearance of endog-enous organic cations such as histamines and monoamine transmitters.In addition, gene association study in the Japanese cohort also demon-strated that OCT3 polymorphisms are related to the development ofpolysubstance use with methamphetamine dependence [204]. Howev-er, it was noticed that the correction between the transport function ofthese variants and the above symptom was not established.

4.4. OCTN1

The cation/carnitine transporter OCTN1 is expressed in multipletissues including the kidney, muscle cells and bone marrow [205]. Itcan transport zwitterions such as L-ergothioneine and L-carnitine, aswell as several organic cationic drugs like TEA, quinidine and verapamilat a pH-dependent and membrane potential-sensitive manner [205,206]. It can operate at both directions in respect to different substrates[205–207]. For instance, in the OCTN1 stably transfected HEK293 cells,an “overshoot” uptake of TEA was observed with an initial outwardlydirected proton gradient [207].

It has been indicated that OCTN1 and OCTN2 polymorphisms are as-sociated with increased incidences of inflammatory bowel diseases,rheumatoid arthritis and asthma [208]; however, the actual contribu-tion of these two genes to such diseases are not conclusive [209]. Themolecular characterisation of OCTN1 genetic variants have been report-ed by us and others (Table 3). Kawasaki et al. revealed that OCTN1-G462E has significantly reduced activity in the uptake of TEA; whileOCTN1-T306I variant retained the full transport function [210]. In2007, Urban et al. identified six nonsynonymous variants in a large co-hort with three variants (D165G, R282stop and M205I) have reducedtransport function and the high frequency OCTN1- L503F variantshowed increased TEA uptake, unchanged betaine transport and re-duced gabapentin influx [211,212]. Interestingly, the patients homozy-gous for the OCTN1-L503F variant have decreased renal clearance ofgabapentin, which may lead to therapeutic toxicity due to the accumu-lation of this drug [211]. More recently, we functionally assessed eightnovel OCTN1 genetic variants that identified in 192 Singapore subjects[213]; four variants (R63H, R83P, G482D, and I500N) are dysfunctionalwith the potential to influence the antioxidant capacity in individuals[214].

4.5. OCTN2

OCTN2 distributes in the kidney, heart, brain and placenta, where itmediates the uptake of organic cationic molecules in a sodium-independent manner [215]. It is also a high-affinity transporter to L-carnitine; interestingly, sodium can significantly enhance the L-carnitinebinding to this transporter [215]. Therefore, impaired activity of OCTN2resulted from genetic mutation or drug–drug/herb interactions couldlead to primary systemic carnitine deficiency (SCD). Due to the pivotalrole of carnitine in beta-oxidation of long-chain fatty acids to produceATP, OCTN2 dysfunction can potentially result in a range of diseasessuch as colorectal cancer [216].

We and others have demonstrated the functional consequenceof OCTN2 polymorphisms [215,217–219] (Table 3). Eight genetic vari-ants of OCTN2 were found to have altered transport activity in the

uptake of TEA and/or L-carnitine. Grube et al. indicated that OCTN2 ex-pression is selectively reduced in dilated cardiomyopathy patients[220], although the frequency of OCTN2 variants identified in patientswith cardiomyopathywere not different from that of the normal people[217]. This suggested the presence of possible polymorphisms of OCTN2gene within the promoter region. Interestingly, Angelini et al. indicatedthat OCTN2 genotypes are possibly a predictor of the progression timein gastrointestinal stromal tumors (GIST) patients receiving imatinibtherapy [221]. Consistently, OCTN2 was shown to be one of the SLCtransporters that responsible for the uptake of imatinib using over-expressing HEK293 cells [222]. It will be of great interests that geneticassociation of OCTN2 with GIST patients can be further explored in thefuture, ideally with molecular characterisation of the OCTN2 variantsin respect to their ability in transporting imatinib.

4.6. OCT6

OCT6, also called CT2, was cloned in the testis [223] and hematopoi-etic tissues [224] in 2002. It transports carnitine but not the other classiccationic substrates of OCTs/OCTNs [223]. Later, OCT6 was also found tobe associated with the uptake of anti-cancer agents, doxorubicin andcisplatin in cancer cells [225,226]. Furthermore, OCT6 polymorphismswere reported to be associated with the inter-patient variations ofdoxorubicin pharmacokinetics in an Asian breast cancer patient cohort[227]. Therefore, it is required that OCT6 polymorphisms identified inthe patients can be functionally assessed to providemolecular evidencetowards the in vivo observation.

5. Conclusions

It is commonly recognised that multiple factors includingmetabolising enzymes and influx/efflux transporters, influencing thepharmacokinetic performance of drugs. SLC transporters, as the maininflux drug transporters, significantly contribute to the absorption,distribution and elimination of pharmaceutical agents. Genetic poly-morphisms have been identified in a number of SLCs, some of which re-sult in dysfunctional variant transporters; consequently, impact on drugsafety and toxicity in individuals. However, current pharmaceutical re-search primarily focuses on either the association of transporter poly-morphisms with drug pharmacokinetics, or molecular assessment oftransporter genetic variants in the context of specific substrate uptake,which independent approaches are not sufficient in providing theoret-ical evidence to support the clinical observation. It is highly desired thatfuture studies could target to establish the correlation between pheno-types and genotypes. This can be achieved by integrating in vitro exper-imental results into human studies so as to form a solid foundation forgenome-based pharmacotherapy.

Acknowledgements

The authors would like to acknowledge the National Health andMedical Research Council of Australia (GNT1025101) for financialsupport.

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