Pharmacogenetics of drug transporters in the …...Zurich Open Repository and Archive University of Zurich Main Library Winterthurerstr. 190 CH-8057 Zurich Year: 2011 Pharmacogenetics

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University of ZurichMain LibraryWinterthurerstr. 190CH-8057 Zurichwww.zora.uzh.ch

Year: 2011

Pharmacogenetics of drug transporters in theenterohepatic circulation

Stieger, B; Meier, P J

http://www.ncbi.nlm.nih.gov/pubmed/21619426.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Stieger, B; Meier, P J (2011). Pharmacogenetics of drug transporters in the enterohepatic circulation.Pharmacogenomics, 12(5):611-631.

http://www.ncbi.nlm.nih.gov/pubmed/21619426.Postprint available at:http://www.zora.uzh.ch

Posted at the Zurich Open Repository and Archive, University of Zurich.http://www.zora.uzh.ch

Originally published at:Stieger, B; Meier, P J (2011). Pharmacogenetics of drug transporters in the enterohepatic circulation.Pharmacogenomics, 12(5):611-631.

Pharmacogenetics of drug transporters in theenterohepatic circulation

Abstract

This article summarizes the impact of the pharmacogenetics of drug transporters expressed inthe enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. Therole of pharmacogenetics in the function of drug transporter proteins in vitro is now wellestablished and evidence is rapidly accumulating from in vivo pharmacokinetic studies, whichsuggests that genetic variants of drug transporter proteins can translate into clinically relevantphenotypes. However, a large amount of conflicting information on the clinical relevance ofdrug transporter proteins has so far precluded the emergence of a clear picture regarding therole of drug transporter pharmacogenetics in medical practice. This is very well exemplifiedby the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to developpharmacogenetic models with sufficient predictive power to allow for translation into drugtherapy. This will require a combination of pharmacogenetics of drug transporters, drugmetabolism and pharmacodynamics of the respective drugs.

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Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Bruno Stieger1 and Peter J. Meier2

1) Division of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich,

Switzerland; 2) University of Basel, Basel, Switzerland

Corresponding author:

Peter J. Meier-Abt, MD

University of Basel

Petersplatz 35

4003 Basel

Switzerland

Email: [email protected]

Phone: +41-61-267-2735

Fax: +41-61-267-1239

Key Words

Intestine, liver, enterohepatic circulation, pharmacokinetics, drug disposition, adverse drug

events

mailto:[email protected]

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Summary

This review summarizes the impact of pharmacogenetics of drug transporters expressed in the

enterohepatic circulation on pharmacokinetics and pharmacodynamics of drugs. The role of

pharmacogenetics in the function of drug transport proteins in vitro is now well established

and evidence is rapidly accumulating from in vivo pharmacokinetic studies that genetic

variants of drug transport proteins can translate into clinically relevant phenotypes. However,

a lot of conflicting information on the clinical relevance of drug transport proteins has so far

precluded the emergence of a clear picture on the role of drug transporter pharmacogenetics in

medical practice. This is very well exemplified by the case of p-glycoprotein (MDR1,

ABCB1). The challenge is now to develop pharmacogenetic models with a sufficient

predictive power for translation into drug therapy. This will require a combination of

pharmacogenetics of drug transporters, drug metabolism and pharmcodynamics of the

respective drugs.

1. INTRODUCTION

Orally administered drugs have to pass several anatomical and functional barriers

before they reach their targets. These barriers include the uptake across the intestinal wall, the

passage through the liver as well as the passage through other organ barriers such as for

example the blood brain barrier or the blood testis barrier [1-3]. After their action, drugs are

eliminated from the body via the liver or the kidney with or without prior biotransformation

[4]. Hence, throughout their entire life-span in the body, drugs need to cross cell membranes

multiple times. Biological membranes are very tight barriers for most molecules and even

limit the crossing of lipophilic substances such as cholesterol or long chain-fatty acids. This

latter point is illustrated by the observations that Nieman-Pick C1-like 1 protein is located in

the apical membrane of enterocytes and involved in cholesterol absorption [5] or that uptake

of very long-chain fatty acids into peroxisomes involves the role of the ATP binding cassette

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(ABC) transporter ABCD1 [6] (see table 1 for a list of transporters and their subcellular

expression covered in this review). The number of drug transporters is high and the

knowledge on their pharmacogenetics is rapidly evolving [7-15].

This review focuses on drug transporters in the enterohepatic circulation, as the

intestine and the liver are two key organs in drug disposition (figure 1). The prototypic,

endogenous substrates of the enterohepatic circulation are bile salts [16-18]. Bile salts are bile

acids conjugated with taurine or glycine. They are secreted by hepatocytes into primary bile

and shipped via the bile duct into the duodenum, where they promote absorption of lipids and

fat soluble vitamins. Along the intestinal tract, bile salts are reabsorbed to greater than 95 %

and shipped back via the portal circulation to the liver, where they are again taken up into

hepatocytes. A small portion of bile salts is deconjugated in the intestine and reconjugated in

hepatocytes. Therefore, bile salts can be considered model substances for drugs undergoing

enterohepatic circulation [19].

Drugs taken up into hepatocytes may be excreted into bile either unchanged or as

biotransformed metabolites and delivered to the intestine. For example, pravastatin is a

substrate of organic anion transporting polypeptides (OATPs) and of the multidrug resistance

associated protein 2 (MRP2), which are expressed in the basolateral and canalicular

membrane of hepatocytes, respectively [20, 21]. Hence, in the liver pravastatin is vectorially

excreted bile and in the intestine biliary excreted pravastatin is reabsorbed and, thus subjected

to enterohepatic circulation. Another example is mycophenolic acid, which is widely used as

an immunosuppressant in solid organ transplantation. Mycophenolate's pharmacokinetic is

affected by hepatic and renal impairment [22]. It is glucuronidated in different organs

including the liver into its pharmacologically inactive form 7-O-mycophenolate-glucuronide.

Recently, it has been demonstrated that the glucuronide of mycophenolate, but not the parent

compound, is a substrate of OATP1B1 expressed at the basolateral membrane of hepatocytes

(figure 1)[23]. This metabolite is excreted into bile via rat Mrp2 (and therefore likely also via

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human MRP2) [24]. In the intestine, the metabolite is deconjugated and mycophenolate is

taken up again. This enterohepatic recycling may contribute to about 40 % of mycophenolate

exposure [22]. Interruption of the enterohepatic circulation can also help to control toxicity of

drugs such as phenprocumon [25, 26], further supporting the clinical importance of

enterohepatic drug circulation.

2. DRUG TRANSPORTERS IN THE INTESTINE

Enterocytes are protected from the luminal contents of the intestine by a layer of

mucus and by a glycocalix, which overlays directly the microvilli of enterocytes [27]. The

glyocalix is the first boundary, which drugs have to cross prior to their access to the brush

border membrane of enterocytes. Altered composition of the glycocalix has been

demonstrated in a rat model to influence the absorption of drugs such as for example

acetamide [28]. In addition, intestinal absorption in patients receiving chemotherapy is altered

in part due to a change of the glycocalix [29]. The glyocalix is rich in fixed negative charges,

which in turn lead to an acidic microenvironment [30] and an increase in the local

concentration of sodium ions [31]. Hence, the specific local environment facing the brush

border of enterocytes may potentially impact drug uptake [32], for example by changing the

hydrophobicity of drugs containing carboxylic acid groups. So far, to the best of our

knowledge, the pharmacogenetics of the intestinal glycocalix has not been investigated.

Drug transporters are expressed at distinct levels in different parts of the intestine and

involve members of the solute carrier (SLC) super family as well as members of the ATP-

binding cassette (ABC) transporter superfamily [10, 33-35]. In the human intestine SLC

superfamily members include the uptake transporters, CNT1, CNT2, OAT2, OATP1C1,

OATP2B1, OATP3A1, OATP4A1, OATP4B1, OCT1, OCT3, OCTN1, OCTN2, MCT1,

MCT2, PEPT1, PEPT2 (table 1) [35-40]. Unfortunately, many studies are based only on

mRNA expression leaving the subcellular localization and surface distribution of the

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respective transporters unknown (table 1). The situation is further complicated by the fact that

antibodies and immunohistochemical procedures used for subcellular transporter localization

have often not been validated [41], which has lead to conflicting results as for example in the

case of OATP1A2. While one group found intestinal expression of OATP1A2 [42], other

groups could not detect it in the human intestine [36, 38, 39]. In addition, although several

different ABC transporters such as ABCG2, MDR1, MRP1-7 [10, 33-35, 37, 38, 43] have

been reported to be expressed in human intestine (table 1), the exact subcellular localization

of many of these transporters has not been worked out.

PEPT1, MDR1, MRP2 and ABCG2 have definitively been assigned to the brush

border (apical) plasma membrane domain [33], while MRP3 is expressed at the basolateral

membrane of enterocytes (figure1 ; table 1). PEPT1 mediates for example the absorption of β-

lactam antibiotics, angiotensin converting enzyme inhibitors, and antiviral drugs among

others [44]. In contrast, apical MDR1, MRP2 and ABCG2 act as efflux systems and actually

prevent the entry of their substrates into enterocytes thus reducing the systemic bioavailability

of their substrates [35]. This has been exemplified in an elegant study for the MDR1 substrate

digoxin in humans [45]. MDR1 transports a wide variety of xenobiotics including anticancer

drugs, antifungals, antihistamines, antihypertensives, drugs acting in the central nervous

system, cardiovascular drugs, HIV-1 protease inhibitors and various immunosuppressants [12,

35, 43, 46-48]. The general theme of MDR1 substrates is that they are structurally unrelated

but are either neutral or positively charged hydrophobic compounds. MDR1 has a rather large

pocket for binding its substrates explaining the large variety of substances that it can

accommodate [49]. MRP2 mediates efflux of non-metabolized drugs, xenobiotics and of

numerous phase II metabolites [8, 43, 50, 51]. ABCG2 substrates include a long list of

chemotherapy agents, antiviral drugs, statins, calcium channel blockers, steroid metabolites

and toxins such as aflatoxin and ochratoxin A [52-54]. Very interestingly, urate has been

identified as a possible transport substrate of ABCG2 [55] in a genome wide association study

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aimed at the identification of susceptibility genes for gout [56]. MRP3 seems to transport

predominantly drug metabolites as well as methotrexate [57].

3. DRUG TRANSPORTERS IN THE LIVER

The liver is an essential organ for detoxification and drug metabolism and is situated

between the intestine and the systemic circulation (figure 1). Consequently, it is equipped

with an array of uptake systems for drugs and xenobiotics in the basolateral plasma membrane

of hepatocytes, which are in contact with the blood plasma via the space of Disse and the

fenestrated endothelium of the sinusoids (table 1, figure 1). These hepatocytic uptake

transporters belong mostly to the SLC superfamily, which have a major impact on the first

pass clearance of drugs. The transporters include OATP1B1, OATP1B3, OATP2B1, OAT2

and OAT7 for anionic compounds and OCT1, OCT3, OCTN1 and OCTN2 for cationic

compounds [4, 35, 38, 50, 58-60](table 1). Typical drugs transported by OATPs are relatively

lipophilic anionic drugs such as statins, antibiotics, sartans, angiotensine converting enzyme

inhibitors and anticancer drugs [61]. OATs also mediate transport of more hydrophilic anionic

drugs including angiotensin converting enzyme inhibitors, diuretics,, antibiotics, antiviral

drugs, histamine receptor 2 blockers and nonsteroidal anti-inflammatory drugs [62] Typical

drug classes handled by the organic cation transporters are anaesthetics, antiallergics,

antiarythmics, antidepressants, antihypertensives, non steroidal anti-inflammatory drugs,

antimalarials and antineoplastics [63]. In addition, there are some nucleoside transporters

expressed in human liver such as CNT1, ENT1 and ENT2 [4, 35, 38, 40, 60, 64]. These

transporters are highly relevant in treatment of viral hepatitis with nucleoside analogues [65].

Finally, NTCP, which predominantly transports glycine and taurine conjugated bile salt

uptake system, and to a lesser degree also some drugs such as for example rosuvastatin [18].

Once the drugs have been biotransformed in the liver, the corresponding metabolites

have to be eliminated from hepatocytes. This is achieved on one hand by the basolateral

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export pumps MRP3 and MRP4, which direct their hydrophilic substrates towards renal

elimination and on the other hand by a variety of canalicular excretory systems, which excrete

more lipophilic drugs and drug metabolites into bile and direct them towards fecal elimination

(table 1, figure 1) [35, 38, 43, 50, 66]. MRP3 and MRP4 export, in addition to endogenous

substrates, mainly drug metabolites and some antimetabolites [57]. MRP6, which is also

expressed in the basolateral hepatocyte membrane does not seem to be involved in the

transport of drugs or their metabolites [67]. In fact, the exact physiologic function of MRP6

has remained elusive so far [68]. At the canalicular membrane MDR1, which is restricted to

the canalicular membrane of hepatocytes, mediates the export of neutral and cationic

compounds into bile [4, 35, 38, 66]. Recently, a new canalicular drug transporter called

multidrug and toxin extruder (MATE) has been identified [69]. The exact role of MATE1 for

biliary drug elimination needs to be worked out in more details, but it may be involved in

handling of antiarrhythmics, antibacterials and antimalarials [63]. MRP2 represents the main

biliary export pump for phase II drug conjugates [70] and ABCG2 has been shown to be

involved in the biliary elimination of some anticancer drugs [54]. Finally, the canalicular bile

salt export pump BSEP is a crucial "bottle neck" for biliary secretion of conjugated bile salts

[18, 71]. So far, only the statin pravastatin has been identified as BSEP substrate [18, 72].

However, BSEP is inhibited by a great variety of drugs and, thus, plays a crucial role in the

pathogenesis of drug induced cholestatic liver disease [18, 73-75]. MRP3 mediates biliary

phospholipid secretion [76], ABCG5/ABCG8 facilitates canalicular cholesterol release [77]

and the p-type ATPase ATP8B1 is essential for canalicular bile formation and probably acts

as an animophospholipid flipase [78]. None of these latter transporters has been shown to be

involved in drug and/or drug metabolite transport.

4. PHARMACOGENETICS OF INTESTINAL DRUG TRANSPORTERS

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In the following, the pharmacogenetics of only those transporters that have been

clearly localized at the subcellular level will be covered. These transporters include PETP1,

MDR1, MRP2 and ABCG2, which are localized on the apical (luminal) and MRP3 that is

expressed on the basolateral (blood faced) side of enterocytes and/or hepatocytes (table 1,

figure 1). The functional consequences in vitro if the various transporter polymorphisms are

summarized in table 2. Table 3 gives a specific overview about the in vivo consequences of

MDR1 polymorphisms. To our knowledge, so far no studies on the impact of SLC28 or

SLC29 family members on pharmacogenetics of drugs have been published. Therefore, these

transporters are not covered here, but the impact of their genetic variants in in vitro functional

assays has been reviewed [79].

4.1. Apical Intestinal Drug Transporters

PEPT1 (SLC15A1):

Using a PCR based sequencing approach, 57 genetic variations in SLC15A1 from 48

unrelated Japanese individuals were identified [80]. Among these, 51 were single nucleotide

polymorphisms (SNPs) including two nonsynonymous (p.G419A and p.V459I). However, no

functional assays were reported. The analysis of 44 ethnically different individuals identified

13 SNPs, of which nine were nonsynonymous [81]. They were functionally characterized in

HeLa cells and only p.P586L affected the transport capacity of PEPT1 (table 2). Interestingly,

similar to the Japanese cohort mentioned above, the SNPs p.G419A and p.A449 were also

found in this study. In another study, 247 ethnically variable individuals displayed 38 SNPs

[82]. Eight of the nine nonsynonymous variants were expressed in CHO cells, but only

p.F28Y displayed reduced transport activity (increased Km), while the others remained

unchanged. To our knowledge, so far no clinical studies have investigated the impact of these

polymorphisms on the pharmacokinetics of PEPT1 substrates [33].

MDR1 (ABCB1):

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Due to its location in the apical or brush border membrane of enterocytes, MDR1 can

have a great impact on the bioavailability of certain drugs [35, 83-85]. Consequently, MDR1

has high clinical relevance in drug therapy and the impact of genetic polymorphisms of

ABCB1 on drug disposition as well as drug efficacy has been studied extensively and covered

in multiple reviews [10, 12, 46-48, 86-92]. Overall, more than 50 polymorphisms,

insertions/deletions and changes in the promoter region have been reported for ABCB1

encoding MDR1 [12, 48, 93]. A series of nonsynonymous polymorphic variants have been

characterized functionally. As indicate in table 2, even identical genetic MDR1 variants lead

to different functional activities in different expression and/or assay systems, illustrating the

importance of the types of experimental approaches used such as for example direct transport

measurements or indirect measurements of extrusion of chemically modified MDR1

substrates. Among the reported polymorphisms, c.1236C>T (synonymous), c.2677G>T/A,

and c.3435C>T (synonymous) are common with frequencies of 0.41, 0.42/0.02 and 0.54 and

do not display a distinct pattern in various ethnic groups [12, 47, 48]. They are in strong

linkage equilibrium. The C.1236T/2677T/3435T haplotype was found in 32 % of Caucasians,

27 % of Asian-Americans, 35 % Mexican-Americans and 33 % in Pacific-Islanders (ranging

from 100 to 6 individuals), but only in 5 % of African Americans (99 individuals) [94] as well

as in 69 % an Ashkenazi Jewish population (101 individuals) [95]. Among these three

polymorphisms, the c.2677G>T/A (p.A893S/T) is nonsynonymous but its effects on MDR1

transport function are inconsistent between various studies (table 2) [48, 93]. The

synonymous c.3435C>T polymorphism has been associated with lower MDR1 protein

expression [96] and has been extensively investigated in vitro and in vivo. The in vitro

experiments yielded conflicting results but subtle functional changes of its gene product have

been reported [93]. Similarly, the in vivo studies on drug disposition yielded conflicting

qualitative and quantitative results, ranging from increased, unchanged to even lowered

plasma levels of model drugs [10, 46, 48, 90, 91, 97]. It is therefore not surprising that the

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pharmacodynamic consequences are also highly variable [46]. Several recent meta analyses of

studies investigating the c.3435C>T polymorphism are listed in table 3. Digoxin

pharmacokinetics were not affected by c.3435C>T [98] and the response to anticonvulsant

drugs exhibited also no association with this polymorphism [99, 100]. In contrast, the effects

on cyclosporine pharmacokinetics are more complex: Overall, there was no effect of the

c.3435C>T ABCB1 polymorphism on the pharmacokinetic parameters, although the total

cyclosporine bioavailability (AUC0-12) was slightly reduced (table 3) [101]. Furthermore, the

c.3435C>T polymorphism was found to be associated with a minimal increase in the risk for

ulcerative colitis or breast cancer in Caucasians [102-104]. Taken together, the c.3435C>T

polymorphism does no seem to have a significant impact on drug disposition, nor does it

appear to cause a significant risk for intestinal disease processes. Several reasons may account

for the rather negative or at least conflicting findings: First, the ABCB1 gene contains over 50

haplotypes [94] displaying ethnicity dependent frequencies. Many studies so far are based on

populations of mixed ethnicities and did not analyse for detailed haplotypes (table 3). Second,

many MDR1 substrates are also substrates of cytochrome P450 isoenzymes, especially of

CYP3A4 [105, 106]. Hence, studies analyzing the exact interplay between CYP3A4

dependent drug metabolism and MDR1 mediated drug transport are needed to better

distinguish between pharmacogenetics of drug metabolism and pharmacogenetics of MDR1

transport functions. Third, MDR1 as well as CYP3A4 are both subject to drug-drug

interactions at their substrates binding sites and, more importantly, are also highly regulated at

the expression level by drugs, natural products and food components, all of which can exhibit

a major impact on the bioavailability of MDR1 substrates [45, 107-109]. Both, pregnane-X-

receptor PXR and constitutive androstane receptor CAR control the transcription of ABCB1

and, hence, the expression of MDR1 [110-113]. These latter factors may indeed have a greater

impact on the disposition of MDR1 substrates than ABCB1 polymorphisms. Fourth, many of

the reported studies have limited power for the detection of subtle interindividual changes in

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drug disposition due to limited sample [114, 115]. And fifth, studies related to the impact of

c.3435C>T polymorphism of ABCB1 on clinical phenotypes have not been replicated in

independent large cohorts to confirm findings [116]. Thus the definite elucidation of the

overall significance of most ABCB1 polymorphisms reported so far requires further

investigations.

ABCG2 or BCRP (ABCG2)

ABCG2 encodes BCRP or ABCG2 and is known to display over 50 different

polymorphic positions [52, 54, 117]. Most of the SNPs have minor frequencies with the

exception of c.34G>A and c.421C>A, which have an ethnicity dependent frequency of up to

0.64 and 0.36, respectively [54]. The impacts of these two polymorphisms are summarized in

table 2. It becomes clear that the results of different investigations vary, which in part may be

explained by the fact that these polymorphisms also affect the level of expression and exact

plasma membrane localization of the transport proteins in the model systems used. As for

ABCB1, the findings of an impact of ABCG2 polymorphisms on pharmacokinetics of drugs or

outcomes of cancer therapy are contradictory [7, 33, 53]. An example of contradictory

findings is irinotecan, where, the ABCG2 c.421C>A polymorphism has been reported to be

associated with an increased incidence of neutropenia in a Japanese cohort of cancer patients

[118]. Another study reported an association between an intronic polymorphism and severe

irinotecan induced myelosuppression [119]. In contrast, two further studies did not find any

association with irinotecan disposition [120, 121], but Han and coworkers found an

association with response rate and progression-free survival [121]. Although these

discrepancies are difficult to understand, the might reflect the complex metabolism of

irinotecan, the wide tissue distribution of ABCG2 and last but not least the limited number of

patients included in their perspective studies [53, 122].

MRP2 (ABCC2)

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Multiple polymorphisms and mutations in the ABCC2 gene are known [8, 33, 48, 70].

As nonfunctional MRP2 leads to the Dubin-Johnson syndrome, a long list of mutations with

very low frequencies has been published [70]. 11 polymorphisms display ethnicity variations

in frequency rates [48, 70]. Among the reported SNPs, c.1249G>A, c.2366C>T, c.3542G>T,

c.3563T>A, c.3972C>T and c4544G>A are nonsynonymous, whereby c.3972C>T is in

linkage disequilibrium with c.-25C>T and c.4544GA with c.3563T>A. Some of these

nonsynonymous variants have bee characterized in heterologous expression systems and do

no show overt changes in activity but they might exhibit reduced protein expression (table 2).

Studies focusing on the effect of ABCC2 polymorphisms on pharmacokinetics of drugs are

rare, but they have been associated with alterations of methotrexate and irinotecan disposition

[8, 48]. For example, in a pharmacokinetic study of high-dose methotrexate treatment of

pediatric acute lymphoblastic anemia, the c.-24T allele of ABCC2 was associated with

significantly elevated AUC36-48 in females [123]. This finding illustrates that polymorphisms

can have gender specific outcomes. The functional consequence of this promoter variant has

been postulated to be lower protein expression. One study included 67 cancer patients that

were treated with irinotecan. Apparently lower irinotecan exposure was found in individuals

with the c.1249A allele of ABCC2. [124]. In addition, polymorphisms of ABCC2 have been

associated with irinotecan induced side effects such as diarrhea [8, 48]. In a trial with 167

patients, carriers of the ABCC2*2 haplotype (c.-1549G, c.-1019G, c.-24C, c.1249G, IVS26

c.-34T, c.3972C) had significantly less diarrhea [125]. Another study with 87 patients found

an association between an enhanced enterohepatic circulation of the drug mycophenolate with

the c.-24T allele [126]. Genetic variants of ABCC2 may also affect the detoxification capacity

of the liver as suggested by a Korean study including 94 cases of toxic hepatitis, mostly due to

herbal remedies [127]. Other ABCC2 variants might be associated with an increased

susceptibility to diclofenac induced liver injury [128].

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4.2 Basolateral Intestinal Drug Transporters

MRP3 (ABCC3)

Numerous intronic and exonic polymorphisms have been published for ABCC3 [7,

129-132]. The functional consequences of several variants are presented in table 2. With the

exception of p.S346F and p.S607N, which have almost completely lost their functional

activity, all other variants display normal or even slightly increased transport function. A

study investigating the predisposition and treatment outcome in 139 patients (Jews and Arabs)

in comparison with 217 controls identified the c.-211C>T variant of ABCC3 as a prognostic

marker for acute myeloid leukemia [133]. In contrast, no association of ABCC3

polymorphisms could be associated with colon cancer [134]. In 349 Caucasian patients with

primary lung cancer, c.-211C>T carriers had a significantly worsened progression-free

survival, if they displayed with small cell lung cancer [135]. Studies investigating the role of

MRP3 SNPs on drug pharmacokinetics seem to be absent so far.

5. PHARMACOGENETICS OF LIVER DRUG TRANSPORTERS

Similar to intestinal transporters, this section will only cover those liver transporters,

the subcellular localization of which has been characterized on the two polar plasma

membrane domains of hepatocytes (table 1, figure 1). The functional consequences of the

various polymorphisms are summarized in table 2. Furthermore, the pharmacogenetics of

transporters that are expressed in the intestine as well as in the liver (e.g. MDR1, MRP2,

MRP3, ABCG2), have already been summarized in section 4 and, therefore, will not be

repeated here.

5.1 Basolateral Drug Transporters in Hepatocytes

OATP1B1 (SCL1B1)

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The liver is the target organ of statins. They are widely prescribed in medicine, show

considerable differences in their pharmacokinetic properties and can cause side effects,

mainly myotoxicity, which are sometimes severe [136-138]. As OATPs are statin

transporters, the impact of SLCO gene polymorphisms on statin disposition has been

extensively studied with a focus on SLCO1B1. [8, 137, 139-142]. A first publication on

SCLO1B1 polymorphisms investigated the functional consequences of 14 nonsynonymous

polymorphisms identified by sequencing the SLCO1B1 gene in 42 European-Americans and

22 African-Americans (table 2) [143]. Among these allelic frequencies the variants

c.388G>A, c.463A>C, c.521T>C, c.G1463G>C and c.2000A>G are rather frequent and

ethnicity dependent. Some of the investigated protein variants are associated functionally with

changes in Km, in vmax and/or in altered transport protein expression (table 2). The authors

also investigated various other complex haplotypes. They found that OATP1B1*1c (p.R153K,

p.D241N) has normal activity, OATP1B1*3 (p.V82A, p.E156G) exhibits an increased Km

and reduced plasma membrane expression, OATP1B1*12 (p.V73L, p.D655G), OATP1B1*13

(p.V82A, p.E156G, p.E667G) has an increased Km and OATP1B1*14 (p.N130D, p.P155T)

has an unaltered activity if assessed for transport of the endogenous substrate estrone-3-

sulfate [143]. If rifampicin was used as substrate, the same qualitative results were obtained

[144]. Individuals homozygous for the CC allele of c.521T>C (p.174A) have a significantly

higher area under the plasma concentration time curve than individuals with a TT allele [141].

A common adverse action of statins is myotoxity, which depends on the serum level of statins

[136, 145]. The association of OATP1B1 with statin myotoxity has been confirmed by a

recent landmark paper reporting a genome-wide association study with patients on a high dose

simvastatin regimen (80 mg daily), which associated 60 % of the patients with myopathy to

the c.521T>C polymorphism of SCLCO1B1 [146]. Very importantly, this association could be

replicated also in a population of patients on lower daily simvastatin doses (40 mg) [146].

Moreover, the 174A variant of OATP1B1 displayed a slight reduction of the cholesterol

15

lowering effect of simvastatin. Hence, the SLCO1B1 polymorphism c.521T>C appears to be

the most thoroughly documented polymorphism in the area of drug transporter

pharmacogenetics. Besides statins, a considerable number of additional drugs such as for

example antidiabetics, anticancer drugs, immunosuppressants, sartans or antibiotics have been

found to display pharmacokinetic differences for different OATP1B1 phenotypes [8, 60, 147].

OATP1B3 (SLCO1B3):

Fewer polymorphisms of SLCO1B3 have been reported so far (table 2). Some of the

nonsynonymous variants reduce the transport function of OATP1B3 in vitro (table 2). In a

study involving 70 renal transplant recipients, a decrease in dose-normalized mycophenolate

concomitant with an increase of dose-normalized serum mycophenolate glucuronide was

associated with the SLCO1B3 c.334G-699A haplotype [23]. In vitro expression the c.334T-

699G variant of SLCO1B3 demonstrated a reduced transport capacity.

OATP2B1 (SLCO2B1):

Very few polymorphisms of SLCO2B1 have been described [60, 61] Two rather

frequent polymorphisms were initially shown to be associated with reduced transport activity

of OAT2B1 for endogenous substrates (table 2), but one polymorphism was later reported to

have increased drug transport activity [148, 149]. Pharmacokinetically, the c.935G>A

polymorphism was demonstrated to lower the plasma level of montelukast, which is used for

treatment of asthma [150], and to affect the sensitivity of OATP2B1 to orange juice [151].

The c.1457C>T variant leads to a significant decrease of fexofenadine exposure, which is

maintained if fexofenadine is coadministered with apple juice [152]. In addition, a

polymorphism in the promoter of SLCO2B1 has been reported [153]. c.-282G>A in

homozygous AA carriers leads to a significant elevation of OATP2B1 mRNA associated with

elevated protein expression in liver biopsies. Based on these findings, it can be expected that

the absorption of other drugs, which are substrates of OATP2B1 are subject to interindividual

variability caused by polymorphisms of SLCO2B1.

16

OCT1 (SLC22A1):

To date, numerous nonsynonymous polymorphisms for SLC22A1 are known (table 2).

Functional characterization of the variants shows that the spectrum of transport alterations

ranges from total absence, no change and significant gains of transporter function. These

functional changes are substrate dependent. In vivo, OCT1 has been intensively investigated

with respect to metformin pharmacokinetics and pharmacodynamics [60]. Polymorphisms of

OCT1 including pR61C result in both, higher exposure to metformin in healthy subjects [154]

and higher glucose and insulin levels under metformin in healthy volunteers [155]. On the

other hand, p.R61C did not show any association with imatinib treatment responses in patients

with chronic myeloid leukemia [156].

OCT3 (SLC22A3):

A detailed summary of studies investigating frequencies of OCT3 polymorphisms is

presented elsewhere [63]. The investigated polymorphisms do either not change the

phenotype or lead to a reduction of transport activity (table 2) [157]. A clinical study found no

association between OCT3 polymorphisms and the renal clearance of metformin in vivo

[158], while another study found a weak association of OCT3 polymorphisms with diabetic

nephropathy and hypertension [159].

OAT7 (SLC22A9):

So far, no polymorphisms have been described for this transporter.

MRP4 (ABCC4):

In a cohort of 48 Japanese, 257 variations were identified in the ABCC4 gene [129].

Among them, three nonsynonymous SNPs without functional characterization were observed.

Later a study in 95 Caucasians reported 74 variations including 10 nonsynonymous ABCC4

alterations [160]. In this latter study, c.912G>T (p.L304R) and c.2269G>A (p.Q757K) were

the same as in the Japanese cohort of 2002. Two recent studies investigated the functional

consequences of 10 variants (table 2) [161, 162]. Most of the changes were minor, with the

17

exception p.G187W, which resulted in a significantly lower protein expression. While direct

in vivo pharmacokinetic studies investigating the potential impact of MPRP4 variants on drug

disposition are missing, several studies found associations between MRP4 variants and drug

concentrations or adverse events. For example, in a study with 30 HIV patients, higher

intracellular tenofovir diphosphate concentration in peripheral blood mononuclear were cells

associated with the c.3436G allele of ABCC4 [163]. Furthermore, in a group of 30 patients

with different ethnicities, the same ABCC4 polymorphism was associated with higher AUC0-

24 and lower renal clearance tenofovir [164], while in another study, no association with

kidney tubular dysfunction was observed [165]. Event-free survival in acute lymphoblastic

leukemia of 275 whites associated significantly with the c.-1393T>C variant and with lower

methotrexate plasma levels, while the c.934A>C variant of MRP4 was associated with lower

event-free survival and with higher frequency of high-grade thrombocytopenia [166].

However, the latter results could not be reproduced in an independent cohort of 519 patients

[167]. In 403 patients with breast cancer, cyclophosphamide-induced adverse drug reactions

were associated with ABCC4 polymorphisms [168], and the c.2269A allele of ABCC4 was

associated with significantly lower white blood cell counts and with higher erythrocyte

content of 6-thioguanine nucleotide in a cohort of 235 patients suffering from inflammatory

bowel disease [169].

5.2 Canalicular Drug Transporters in Hepatocytes

The polymorphisms of the canalicular drug excretory systems that are also expressed

in intestinal epithelial cells (e.g. MDR1, MRP2, ABCG2) have already been dealt with in

section 4 (see above).

MATE1 (SLC47A1):

A screen of DNA samples from 272 ethnically diverse individuals identified six

nonsynonymous and four synonymous variants of SLC47A1 and a screen of 89 Japanese

18

subjects reported 5 nonsynonymous variants of MATE1 [170, 171]. Some of these variants

have been functionally characterized and showed in general reduced functions (table 2).

Clinical studies on the in vivo impact of MATE1 variants have appeared only recently. In a

population of 116 metformin users, the intronic rs2289669G>A was found to be associated

with a reduction hemoglobin A1c, which was interpreted as a reflection of reduced transport

activity of this MATE1 variant [172]. In contrast, another study observed no change in renal

metformin clearance for the same polymorphism [158]. Furthermore, in a stratified group

with the intronic SLC22A1 rs622342CC alleles, the rs2289669G>A of SLC47A1 was again

significantly associated with a lower Hemoglobin A1c.

6. Outlook

The impact of genetic polymorphisms of drug transporters on drug disposition and

pharmacodynamics as well as toxicodynamics has been documented in numerous

publications. However, , most association studies included only small numbers of individuals

and, therefore, reached frequently only marginal statistical significance. Hence, many

unresolved questions remain with respect to the predictive potential of transporter

polymorphisms for drug efficacy and/or adverse drug reactions. There are several reasons for

these remaining discrepancies: First, drug actions as well as toxic effects are not only

determined by pharmacogenetics of drug disposition, but also by the pharmacogenetics of

respective drug targets. This is for example exemplified by the efficacy and side effects of the

anticoagulant drug warfarin, which is influenced by different polymorphisms of the drug

metabolizing enzyme CYP2C9 and of the warfarin target vitamin K epoxide reductase

complex subunit 1 [173]. So far, pharmacogenetic studies addressing all aspects, namely

transport, metabolism and pharmycodynamics of drugs are very infrequent, because they

require very large patient populations to reach statistical significance and to produce

meaningful results [116, 174]. Second, in many instances, conclusive pharmacogenetic studies

19

are blurred by the inclusion of multimorbid patients that are dependent on the simultaneous

intake of multiple drugs (polypharmacy). Third, often the functional effects of individual

genetic polymorphisms on the transport proteins are rather small and therefore lead to only

small alterations in the pharmacokinetics in vivo, which again underlines the need for studies

with large patient populations. Fourth, replication of the findings in several independent large

cohorts would certainly add confidence to the identified polymorphisms. An fifth, some of the

mechanistic models for the disposition of individual drugs may be incomplete and preclude at

this moment practical predictive models. This point can be illustrated by the potentially

hepatotoxic antibiotic drug flucloxacillin: While a genome-wide association study identified

an 80-fold increased risk of the HLA-B*5701 genotype for flucloxacillin induced liver injury

[175], only one out of 500 to 1:1000 patients treated with flucloxacillin will develop liver

injury [176].

Hence, while pharmacogenetics of drug transporters and adverse drug reactions

produced considerable new biological knowledge and yielded many promising clinical results,

there is still a long way to go until reliable models for predicting therapeutic outcome and/or

adverse drug reactions in the general practice of medicine will be reached.

Executive Summary

• The liver and intestine are the key organs of enterohepatic circulation.

• Drug disposition requires a distinct set of drug uptake and drug export transporters in

the intestine and the liver.

• Proof of concept for an impact of genetic variants of selected drug transporters on

pharmacodynamics and toxicodynamics has now been established.

• Pharmacogenetics of some drug transporters has yielded conflicting phenotypic

results.

20

• Independent repetition of pharmacogenetic studies could help to clarify the uncertain

cases.

• Prospective pharmacogenetic studies on therapeutic outcome and/or adverse events are

needed to strengthen the relevance of this field in clinical application.

• Development of new models combining pharmacogenetics of drug disposition and

drug targets is needed to establish the overall predictive potential of pharmacogenetics

for clinical therapy.

Acknowledgement

Bruno Stieger is supported by grant # 31003A_124652 from the Swiss National Science

Foundation. The authors thank Sarah Steinbacher, scientific illustrator at Multimedia and E-

learning Services, University of Zurich, for the design of figure 1.

21

22

Table 1: Expression and Subcellular Localization of Drug Transporters in Human Small Intestine and Liver

gene name protein name protein

abbreviation

alias mRNA

expression*

subcellular protein localization reference

uptake transporters

SLC28A1 concentrative nucleoside

transporter

CNT1 intestine

liver

enterocytes, apical and lateral

unknown

[177]

[177]

SLC28A2 CNT2 SPNT1 intestine

liver

enterocytes, apical and lateral

unknown

[177]

[177]

SLC29A1 equilibrative nucleoside

transporter

ENT1 intestine

liver

crypt cells, lateral

unknown

[177]

[177]

SLC29A2 ENT2 intestine

liver

crypt cells, lateral

hepatocytes, unknown

[177]

[177]

SLC47A1 multidrug and toxin

extrusion transporter

MATE1 liver hepatocytes, canalicular [69]

SLC16A1 monocarboxylate MCT1 intestine unknown [178]

23

transporter liver unknown [179]

SLC16A7 MCT2 liver unknown [179]

SLC10A1 Na+/taurocholate

cotransporting polypeptide

NTCP LBAT liver hepatocytes, basolateral [180]

SLC22A6 organic anion transporter OAT2 NLT liver unknown [181]

SLC22A9 OAT7 UST3,OAT4 liver hepatocytes, basolateral [182]

SLCO1A2 organic anion transporting

polypeptide

OATP1A2 OATP, OAPT-A liver cholangiocytes [183]

SLCO1B1 OATP1B1 OATP2, OATP-

C, LST-1

liver hepatocytes, basolateral [184]

SLCO1B3 OATP1B3 OATP8 liver hepatocytes, basolateral [185]

SLCO1C1 OATP1C1 OATP-F, OATP-

RP5

intestine unknown [38]

SLCO2B1 OATP2B1 OATP-B, OATP-

RP2

liver hepatocytes, basolateral [186]

SLCO3A1 OATP3A1 OATP-D, OATP- intestine unknown [36]

24

RP3 liver unknown [36]

SCLO4A1 OATP4A1 OATP-E, OATP-

RP1

intestine

liver

unknown

unknown

[36]

[36]

SLCO4B1 OATP4B1 OATP-H intestine unknown [38]

SLC22A1 organic cation transporter OCT1 liver hepatocytes, basolateral [187]

SLC22A3 OCT3 EMT intestine

liver

unknown

hepatocytes, basolateral

[187]

[187]

SLC22A4 cation and carnitine

transporter

OCTN1 ETT intestine unknown [188]

SLC22A5 OCTN2 CT1,CDSP intestine unknown [188]

SLC15A1 peptide transporter PEPT1 PECT1 intestine enterocytes, apical [189]

SLC15A2 PEPT2 intestine unknown [38]

export transporters

ABCG2 ABCG2 ABCG2 BCRP, ABC-P intestine

liver

enterocytes, apical

hepatocytes, canalicular

[190]

[190]

25

ABCB1 multi drug resistance

protein

MDR1 p-glycoprotein, p-

gp

intestine

liver

enterocytes, apical


[191]

[191]

ABCC1 multidrug resistance-

associated protein

MRP1 intestine unknown [192]

ABCC2 MRP2 cMOAT intestine

liver

enterocytes, apical


[193]

[194]

ABCC3 MRP3 intestine

liver

enterocytes, basolateral


[195]

[196]

ABCC4 MRP4 intestine

liver

unknown


[197]

[198]

ABCC5 MRP5 intestine unknown [197]

AABC6 MRP6 intestine

liver

unknown


[197]

[199]

ABCC10 MRP7 intestine unknown [200]

3) mRNA expression is indicated for tissues or cells with positive mRNA signals.

26

More informations: For members of the SLC superfamily of transporters: www.bioparadigms.org/slc/menu.asp; for ABC transporters

http://nutrigene.4t.com/humanabc.htm.

27

Table 2: In vitro Functional Characterization of Genetic Drug Transporters Variants in Human Small Intestine and Liver

gene name transporter single nucleotide

polymorphism

protein population size in vitro function reference

intestinal uptake

transporters

SLC15A1 PEPT1 p.P586L

44 individuals

reduced vmax [81]

SLC15A1 PEPT1 p.F28Y 247 individuals increased Km [82]

intestinal efflux

transporters

ABCB1 MDR1 c.571G>A p.G191R n/a reduced drug resistance [201]

ABCB1 MDR1 c.1199G>A p.S440N n/a reduced activity (substrate dependent) [202]

ABCB1 MDR1 c.11199G>A

c.1199G>t

p.S440N

p.S440I

n/a

n/a

increased drug resistance

reduced drug resistance

[203]

ABCB1 MDR1 c.1292-3GT>TG p.C431L n/a reduced drug resistance [204]

28

ABCB1 MDR1 c.2005C>T p.R669C n/a reduced substrate affinity [202]

ABCB1 MDR1 c.2547A>G p.I849M n/a increased transport activity [202]

ABCB1 MDR1 c.2677G>T p.A893S 60 individuals lower intracellular digoxin accumulation [205]

ABCB1 MDR1 c.2677G>T

c.2677G>A

p.A893S

p.A893T

n/a

n/a

unchanged

unchanged

[206]

ABCB1 MDR1 c.2677G>T p.A893S 46 individuals no change in rhodamine 123 efflux from

peripheral blood lymphocytes

[207]

ABCB1 MDR1 c.2667G>T p.A893S n/a reduced transport function [208]


c.2677G>A

p.A893S

p.A.893T

n/a

n/a

increased transport function

increased transport function

[209]


c.2677G>A

p.A893S

p.A.893T

n/a

n/a

increased activity (substrate dependent)

increased substrate affinity and transport

activity

[202]

ABCB1 MDR1 c.2667G>T p.893S 48 individuals no change in rhodamine 123 efflux

activity in peripheral blood mononuclear

cells

[210]

29

ABCB1 MDR1 c.2956A>G p.M986V n/a increased transport activity [202]

ABCB1 MDR1 c.2995G>A p.A999T n/a increased substrate affinity and transport

activity

[202]

ABCB1 MDR1 c.3151C>G p.P1051A n/a increased transport activity (substrate

dependent)

[202]

ABCB1 MDR1 c.3188G>C p.G1063A n/a increased transport activity [202]

ABCG2 ABCG2 c.34G>A p.V12M n/a low transport protein expression in vitro [211]

ABCG2 ABCG2 c.34G>A p.V12M n/a unchanged [212]

ABCG2 ABCG2 c.34G>A p.V12M n/a no change in HEK-293, lowered transport

activity in Sf9 cells in vitro

[213]

ABCG2 ABCG2 c.34G>A p.V12M n/a unchanged [214]

ABCG2 ABCG2 c.421C>A Q141K n/a lower transport protein expression,

normal transport activity

[212]

ABCG2 ABCG2 c.421C>A Q141K n/a reduced drug resistance and lower

ATPase activity

[213]

ABCG2 ABCG2 c.421C>A Q141K n/a reduced drug extrusion [215]

30

ABCG2 ABCG2 c.421C>A Q141K n/a reduced drug resistance [216]

ABCG2 ABCG2 c.421C>A Q141K n/a unchanged [217]

ABCG2 ABCG2 c.421C>A Q141K n/a no change of intracellular porphyrine

accumulation

[218]

ABCG2 ABCG2 c.421C>A Q141K n/a reduced transport activity [219]

ABCG2 ABCG2 c.421C>A Q141K n/a reduced transport activity [55]

ABCG2 ABCG2 c.421C>A Q141K n/a increased Km [220]

ABCC2 MRP2 c.1249G>A p.V417I n/a unchanged [221]

ABCC2 MRP2 c.1249G>A p.S789F n/a reduced transport protein expression, no

change in transport activity

[221]

ABCC2 MRP2 c.1249G>A p.A1450T n/a reduced transport protein expression, no

change in transport activity

[221]

ABCC3 MRP3 c.32G>A p.G11D n/a unchanged [222]

ABCC3 MRP3 c.1037C>T p.S346S n/a reduced transport activity [222]

ABCC3 MRP3 c.1820G>A p.S607N n/a reduced transport activity [222]

ABCC3 MRP3 c.2293G>C p.V765L n/a unchanged [222]

31

ABCC3 MRP3 c.2758C>T p.P920S n/a unchanged [222]

ABCC3 MRP3 c.2768G>A p.R923Q n/a increased transport activity [222]

ABCC3 MRP3 c.3856G>C p.R1286G n/a unchanged [222]

ABCC3 MRP3 c.3890G>A p.R1297H 52 individuals unchanged [131]

ABCC3 MRP3 c.4042C>T p.R1348C n/a increased transport activity [222]

ABCC3 MRP3 c.4094A>G p.Q1365R n/a unchanged [222]

ABCC3 MRP3 c.4141C>A p.R1381S n/a unchanged [222]

liver uptake

transporters

SLCO1B1 OATP1B1 c.218T>C p.F73L n/a increased Km, reduced protein synthesis

and membrane expression

[143]

SLCO1B1 OATP1B1 c.245T>C p.V82A n/a [143]

SLCO1B1 OATP1B1 c.388A>G p.N130D n/a increased Km [143]

SLCO1B1 OATP1B1 c.455G>A p.R152K n/a [143]

SLCO1B1 OATP1B1 c.463C>A p.P155T n/a unchanged [143]

SLCO1B1 OATP1B1 c.467A>G p.E156G n/a [143]

32

SLCO1B1 OATP1B1 c.521T>C p.V174A n/a decreased vmax, reduced transport protein

expression

[143]

SLCO1B1 OATP1B1 c.721G>A p.D241N n/a [143]

SLCO1B1 OATP1B1 c.1058T>C p.I353T n/a increased Km, reduced transport protein

expression

[143]

SLCO1B1 OATP1B1 c.1294A>G p.N432D n/a decreased vmax [143]

SLCO1B1 OATP1B1 c.1385A>G p.D462G n/a decreased vmax [143]

SLCO1B1 OATP1B1 c.1463G>C p.G488A n/a reduced intrinsic clearance, reduced

transport protein expression

[143]

SLCO1B1 OATP1B1 c.1964A>G p.D655G n/a increased Km [143]

SLCO1B1 OATP1B1 c.2000A>G p.E667G n/a unchanged [143]

SLCO1B3 OATP1B3 c.334T>G p.S112A n/a unchanged [223, 224]

SLCO1B3 OATP1B3 c.439A>G p.T147A n/a unchanged [223]

SLCO1B3 OATP1B3 c.699G>A p.M233I n/a reduced transport activity, substrate

dependent alteration of Km

[223, 224]

SLCO1B3 OATP1B3 c.767G>C p.G256A n/a unchanged [223]

33

SLCO1B3 OATP1B3 c.1559A>G p.H520P n/a reduced transport activity [223]

SLCO1B3 OATP1B3 c.1564G>T p.G522C n/a reduced transport activity [224]

SLCO1B3 OATP1B3 c.1679T>C p.V560A n/a reduced transport activity [223]

SLCO2B1 OATP2B1 c.43C>T p.P15S n/a reduced transport activity [149]

SLCO2B1 OATP2B1 c.601G>A p.V201M n/a reduced transport activity [149]

SLCO2B1 OATP2B1 c.1175C>T p.T392I n/a reduced vmax [148]

SLCO2B1 OATP2B1 c.1457C>T p.S486F n/a reduced vmax

increased transport activity

[148]

[149]

SLC22A1 OCT1 c.41C>T p.S14F n/a increased TEA transport

reduced metformin transport

[225]

[155]

SLC22A1 OCT1 c.123C>T

SLC22A1 OCT1 c.181C>T p.R61C n/a reduced transport activity [225, 226]

SLC22A1 OCT1 c.253C>T p.L85F n/a unchanged [225]

SLC22A1 OCT1 c.262C>T p.C88R n/a absent [226]

SLC22A1 OCT1 c.480G>C p.F160L n/a unchanged [225, 226]

SLC22A1 OCT1 c.566C>T p.S189L n/a unchanged TEA transport [225]

34

reduced transport activity [155]

SLC22A1 OCT1 c.659G>T p.G220V n/a absent [225]

SLC22A1 OCT1 c.848C>T p.P263L n/a absent [227]

SLC22A1 OCT1 c.859G>C p.R287G n/a absent [227]

SLC22A1 OCT1 c.1022C>T p.P341L n/a reduced TEA transport

normal metformin transport

[225]

[155]

SLC22A1 OCT1 c.1025G>A p.R342H n/a unchanged [225]

SLC22A1 OCT1 c.1201G>A p.G401S n/a no TEA transport

no MPP transport, reduced TEA transport

[225]

[226]

SLC22A1 OCT1 c.1222A>G p.M408V n/a unchanged [225]

SLC22A1 OCT1 c.1391G>A p.V461I n/a unchanged [225]

SLC22A1 OCT1 c.1386-1170G>A p.G465R n/a absent [225]

SLC22A1 OCT1 c.1386-1100G>T p.R488M n/a unchanged [225]

SLC22A3 OCT3 c.131C>T p.T44M n/a unchanged [157]

SLC22A3 OCT3 c.346G>T p.A116S n/a reduced transport activity [157]

SLC22A3 OCT3 c.1160G>T p.M370I n/a reduced transport activity [228]

35

SLC22A3 OCT3 c.1199C>T p.T400I n/a reduced transport activity [157]

SLC22A3 OCT3 c.1316C>T p.A439V n/a reduced transport activity [157]

SLC22A3 OCT3 c.1423G>A pG475S n/a reduced transport activity [157]

liver efflux

transporters

SLC47A1 MATE1 c.28G>T p.V10L n/a unchanged [171]

SLC47A1 MATE1 c.191G>A p.G64D n/a reduced transport activity, reduced drug

resistance

loss of transport activity

[170]

[171]

SLC47A1 MATE1 c.373C>T p.L125F n/a reduced transport activity (substrate

dependent)

[170]

SLC47A1 MATE1 c.404T>C p.V159M n/a reduced transport activity [229]

SLC47A1 MATE1 c.929C>T p.A310V n/a reduced transport activity [171]

SLC47A1 MATE1 c.983A>C p.D328A n/a reduced transport activity [171]

SLC47A1 MATE1 c.1012G>A p.V338I n/a reduced transport activity (substrate

dependent

[170]

[229]

36

reduced transport activity

SLC47A1 MATE1 c.1421A>G p.N474S n/a reduced transport activity [171]

SLC47A1 MATE1 c.1438G>A p.V480M n/a reduced transport activity, reduced drug

resistance

[170]

SLC47A1 MATE1 c.1490G>C

C.149G>T

p.C497S

p.C497F

n/a reduced, unchanged or increased transport

activities (substrate dependent)

[170, 229]

SLC47A1 MATE1 c.1557G>C p.Q519H n/a unchanged [170]

ABCC4 MRP4 c.232C>G p.P78A n/a increased intracellular drug accumulation

(substrate dependent), lower transport

protein expression

[161]

ABCC4 MRP4 c.559C>T p.G187W n/a increased intracellular drug accumulation,

reduced transport protein expression

slightly reduced function

[161]

[162]

ABCC4 MRP4 c.877A>G p.K293E n/a unchanged [161]

ABCC4 MRP4 c.912G>T p.K304N n/a unchanged [161]

37

unchanged [162]

ABCC4 MRP4 c.1208C>T p.P403L n/a increased intracellular drug accumulation [161]

ABCC4 MRP4 c.1460G>A p.G487E n/a increased intracellular drug accumulation

reduced transport activity (substrate

dependent)

[161]

[162]

ABCC4 MRP4 c.1492A>G p.K498E n/a unaltered [161]

ABCC4 MRP4 c.1667A>G p.Y556C n/a increased transport activity [162]

ABCC4 MRP4 c.2269G>A p.E575K n/a increased transport activity [162]

ABCC4 MRP4 c.2230A>G p.M744V n/a unchanged [161]

ABCC4 MRP4 c.2326G>A p.V776I n/a reduced transport activity [162]

ABCC4 MRP4 c.2459G>T p.R820I n/a reduced transport activity [162]

ABCC4 MRP4 c.2560G>T p.V854F n/a unchanged [162]

ABCC4 MRP4 c.2596A>G p.I866V n/a unchanged [162]

ABCC4 MRP4 c.2867G>C p.C956S n/a reduced intracellular drug accumulation [161]

ABCC4 MRP4 c.3211G>A p.V1071I n/a unchanged [161]

ABCC4 MRP4 c.3425C>T p.T1142M n/a increased transport activity [162]

38

For more information on members of the SLC superfamily of transporters please consult www.bioparadigms.org/slc/menu.asp and for more

information of ABC transporters http://nutrigene.4t.com/humanabc.htm.

39

Table 3: Meta Analyses on the impact in vivo of the c.3435C>T polymorphism of ABCB1on pharmacokinetics, pharmacodynamics and

susceptibility to various diseases

number of

studies

included

number of individuals study subject outcome reference

8 out of 11 121 of different ethnicities digoxin

pharmacokinetics

no difference in exposure, slight reduction in Cmax -0.31 ng/ml

CI (-0.59, -0.02)

[98]

4 out of 5 135 of different ethnicities MDR1 expression no difference [98]

7 out 8 2931 controls, 1743

ulcerative colitis, 2311

Crohn’s diesease

relative risk odds ratio for ulcerative colitis 1.12 CI (1.01, 1.23)

odds ration for Crohn’s disease: 0.99 CI (0.89, 1.10)

[102]*)

6 out of 9 2098 controls, 1530

uilcerative colitis, 1473

Crohn’s disease

relative risk odds ratio for ulcerative colitis 1.17 CI (1.06, 1.31)

no association with Crohn’s Disease

[103] *)

40

3 out of 7 n/a multidrug resistance in

epilepsy

no association [230]

14 out of 17 1036 of different ethnicities cyclosporine

pharmacokinetics

no difference in AUC0-4 and AUC0-inf, AUC0-12 -0.36

(mg/hr/l)mg/kg CI (-0.67, -0.05), no difference in Cmax

[101]

11 out of 12 1725 controls, 1646 patients multidrug resistance in

epilepsy

no association [99]

2 3149 breast cancer patients,

5489 control

hormone therapy

associated breast

cancer risk


9 out of 9 2454 patients, 1542 controls predisposition to

epilepsy


22 3231 drug resistant patients,

2524 drug responders or

healthy controls of different

ethnicities

multidrug resistance in

epilepsy


8 out of28 3829 cases, 6193 controls of breast cancer risk no risk for Asian, Caucasians OR 1.26 CI (1.04, 1.52) for T [104]

41

different ethnicities versus C

*) partial overlap of cohorts

42

Figure Legends

Figure 1: Overview of drug transporters expressed at the membrane boundaries of the

enterohepatic circulation.

43

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3. Leslie EM, Deeley RG, Cole SP: Multidrug resistance proteins: role of P-glycoprotein,

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144. Tirona RG, Leake BF, Wolkoff AW, Kim RB: Human organic anion transporting

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145. Kuncl RW: Agents and mechanisms of toxic myopathy. Curr Opin Neurol 22(5), 506-

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154. Shu Y, Brown C, Castro RA et al.: Effect of genetic variation in the organic cation

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163. Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, Fletcher CV: Clinical and

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187. Nies AT, Koepsell H, Winter S et al.: Expression of organic cation transporters OCT1

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197. Taipalensuu J, Tornblom H, Lindberg G et al.: Correlation of gene expression of ten drug

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