REVIEW ARTICLE

Disposition of metformin: Variability due to polymorphisms

of organic cation transporters
OLIVER ZOLK
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University
of Erlangen-Nuremberg, Fahrstr. 17, 91054 Erlangen, Germany
Abstract
Considerable interindividual variability in clinical efcacy is recognized in the treatment of type 2 diabetes mellitus with
the biguanide metformin. Metformin is a substrate of organic cation transporters, which play important roles in gastroin-
testinal absorption, renal and biliary elimination, and distribution to target sites of substrate drugs. This raises the question
of whether genetic variations in these transporters affect efcacy and risk of adverse events associated with metformin use.
In this review, the pharmacogenetics of metformin is discussed in the light of the most recent literature. Overall, results
from healthy volunteers support the notion that metformin pharmacokinetics can be affected by polymorphisms in genes
encoding organic cation transporters. When considering the glycemic response to metformin in patients, however, the likely
multifactorial nature of metformin response masks the effects of transporter polymorphisms observed in some clinical
studies.
Key words: Diabetes mellitus type 2 , genetic polymorphism , individualized medicine , metformin , organic cation transport proteins ,
pharmacogenetics , SLC22A1 transporter , SLC22A2 transporter , SLC47A1 transporter , SLC47A2 transporter
Introduction
Metformin is the principal biguanide drug that is
used worldwide as an antihyperglycemic agent in
patients with type 2 diabetes mellitus. In addition to
type 2 diabetes, metformin is considered a therapeu-
tic option for other diseases associated with insulin
resistance, such as polycystic ovary syndrome (PCOS)
and gestational diabetes. Metformin is already being
prescribed to patients with PCOS, although it has not
been approved for this indication (1). Its use in ges-
tational diabetes is the subject of current clinical
studies (2).
A major action of metformin is suppression of
hepatic glucose production. Although it has been
used in the clinic since 1957, the direct molecular
target of metformin remains unknown. However,
there has been considerable progress in dening its
pharmacological effects. Inhibition of hepatocyte
glucose production by metformin is mediated by
activation of the enzyme adenosine monophosphate-
activated protein kinase (AMPK), a master sensor,
integrator, and regulator of cellular and body energy
homeostasis (3). AMPK activation is also implicated
as a mechanism for the induction of skeletal muscle
glucose uptake. One potential pathway by which
metformin activates AMPK involves the upstream
serine-threonine kinase 11 (STK11, also known as
LKB1) (4). A recent report provides evidence that
metformin is able to inhibit hepatic gluconeogenesis
also in an LKB1- and AMPK-independent manner
via a decrease in hepatic energy state (5).
In addition to its efcacy in lowering glucose
levels, metformin has the clinical advantages of
inducing mild weight reduction and only a minimal
risk of hypoglycemia. The United Kingdom Prospec-
tive Diabetes Study in 1998 and subsequent studies
and meta-analyses on the effects of metformin on
outcomes conrm that metformin is one of the main
Correspondence: Oliver Zolk, Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University of Erlangen-Nuremberg,
Fahrstr. 17, 91054 Erlangen, Germany. Fax: 49 9131 852277. E-mail: zolk@pharmakologie.uni-erlangen.de
(Received 13 August 2010 ; accepted 14 December 2010 )
Annals of Medicine, 2011; Early Online, 111
ISSN 0785-3890 print/ISSN 1365-2060 online 2011 Informa UK, Ltd.
DOI: 10.3109/07853890.2010.549144
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
2 O. Zolk
therapeutic options in type 2 diabetes mellitus, par-
ticularly in overweight or obese patients, because it
may prevent some macrovascular and microvascular
complications and mortality (6 8). This favorable
action prole has made metformin one of the most
widely prescribed antidiabetic drugs worldwide. In
the US market, metformin recently became one of
the top ten prescribed products; more than 52 mil-
lion prescriptions for its generic formulations were
lled in 2009 (9).
Metformin has some side-effects, principally gas-
trointestinal, which occur in 20% 30% of patients
and require discontinuation of the drug in less than
5% of patients (10). Very rarely, metformin causes
lactic acidosis. The frequency of this side-effect has
been estimated to be 4 5 cases per 100,000 patient
years (11,12). In cases where metformin was impli-
cated as the cause of lactic acidosis, metformin
plasma levels of 5 g/mL were generally found
(13), which is 4 5-fold higher than the maximum
therapeutic steady-state plasma concentration (14).
This suggests that metformin toxicity is associated
with its accumulation in the body.
The antidiabetic response to metformin varies
considerably from patient to patient. Based on clinical
trial experience, metformin reduces HbA
1C
values by
0.8% to 3% (15). In patients using metformin
monotherapy as their rst-ever antihyperglycemic
agent, less than two-thirds of patients achieve a
desired fasting glucose level or the HbA
1C
goal
of 7% (16,17). In routine clinical practice, the non-
response rate to metformin in terms of achieving an
HbA
1C
of 7% within 1 year may be upwards of
50% (18). This incomplete response rate coupled
with the waning effectiveness of metformin over
time that occurs with most oral antidiabetic drugs
(known as secondary failure due to the loss in
insulin secretory capacity) highlights the need
for personalized interventions to maintain tight
glycemic control.
Role of organic cation transporters in
metformin pharmacokinetics
It has been postulated that the observed variability
in metformin response and the occurrence of lactic
acidosis may be partially explained by variability in
the pharmacokinetic disposition of metformin (19).
The bioavailability of metformin is not complete,
and large interindividual differences in bioavail-
ability after oral administration in the range of
20% 70% have been described (20 22). Because
metformin is not metabolized, this broad range
probably reects differences in absorption rather
than rst-pass metabolism. Furthermore, an inverse
relationship between an orally administered dose of
metformin and its bioavailability was observed
(20,22), suggesting the involvement of a carrier-
mediated saturable absorption process (23,24).
Metformin is rapidly distributed following absorp-
tion but does not bind to plasma proteins. Its vol-
ume of distribution is large and can exceed 250 L,
with the intestines, kidneys, and liver being the
major organs of distribution (25,26). The clearance
of metformin is primarily dependent on the single
pathway of renal elimination, as metformin does not
undergo relevant hepatic metabolism or biliary
excretion. Because the renal clearance of metformin
is much higher than the glomerular ltration rate,
active tubular secretion by the kidney is the princi-
pal mechanism of metformin elimination. Accord-
ingly, renal metformin clearance correlates with
excretory kidney function (i.e. creatinine clearance
rate) (20,27). Data suggest that substantial variation
in metformin renal clearance exists, and genetic fac-
tors were found to contribute highly, by more than
90%, to the interindividual variation (28,29). Taken
together, the pharmacokinetic characteristics of
metformin and the inherited differences in met-
formin renal elimination suggest that active trans-
port processes are critical to the disposition of
metformin.
Because metformin is positively charged at phys-
iological pH, it is not expected to diffuse freely
Key messages
Considerable interindividual differences in
pharmacokinetics and clinical efcacy of
metformin are recognized.
Experimental studies in transgenic mice
suggest that organic cation transporters are
important determinants of metformin dis-
position and pharmacologic action.
Several non-synonymous SNPs in the
human genes encoding organic cation trans-
porters were identied and have been found
to cause a loss-of-function phenotype of the
affected transporter in vitro .
Clinical studies suggest that polymorphisms
in organic cation transporter genes, such as
the p.270A S variant in the organic cation
transporter 2 ( SLC22A2 ) gene, may affect
renal clearance of metformin at least in
homozygous carriers of the reduced-func-
tion allele.
An association of dened polymorphisms in
organic cation transporters with glycemic
response to metformin in patients has not
yet been clearly established.
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
Metformin disposition: role of transporter polymorphisms 3
through cell membranes but to cross biological
membranes via carrier proteins. Indeed, metformin
is a substrate for organic cation transporters (OCTs)
in both the kidney and the liver (Figure 1). In
humans, OCT1 (gene name SLC22A1 ) is expressed
in the basolateral membrane of hepatocytes and is
the primary mediator of hepatic metformin uptake
(26,30,31). In contrast, OCT2 (gene name SLC22A2 )
is primarily expressed in the kidney and mediates
uptake of metformin into the proximal tubule cells
(31,32). In addition, metformin has been identied
as a substrate for the multidrug and toxin extrusion
(MATE) antiporters (33). MATE1 (gene name
SLC47A1 ) is strongly expressed in the liver (canali-
cular membrane), kidney (brush border membrane),
and skeletal muscle (34). MATE2 (gene name
SLC47A2 ) is predominantly expressed in the brush
border membrane of renal proximal tubules (34).
Thus, MATE transporters may contribute to renal
excretion of metformin.
The role of these transporters in the disposition
of metformin was established in knock-out mouse
models of Oct1 and Oct2. Oct1 (/) and Oct2 (/)
mice are viable and display no obvious phenotypic
abnormalities (35,36). However, Oct1 (/) mice
show dramatically reduced hepatic uptake of tetra-
ethylammonium (TEA; a prototypical organic cat-
ion) and metformin (26,36,37), whereas renal
excretion of metformin is virtually unchanged
compared with wild-type mice (26). In mouse
hepatocytes, deletion of Oct1 results in a reduction
in the effects of metformin on AMPK phosphoryla-
tion and gluconeogenesis. Thus, OCT1/Oct1 seems
to be an important determinant of metformin
action. When mice are given metformin, the blood
lactate concentration signicantly increases in
wild-type mice, whereas only a slight increase was
observed in Oct1 (/) mice. Thus, Oct1 is respon-
sible for the hepatic uptake of metformin, and the
liver seems to be the key organ responsible for
lactic acidosis (38). In Oct1/2 double knock-out
mice, renal secretion of TEA is abolished, and
plasma levels of TEA are substantially increased
(35). Considering the differences in renal OCT
expression between mice (Oct1 and Oct2) and
human (OCT2), a combined deciency of Oct1
and Oct2 in mice is believed to better reect the
effect of OCT2 deciency in humans. Thus, the
latter study emphasizes the role of OCT2 in renal
elimination of cationic drugs such as metformin.
Targeted disruption of Mate1, which is expressed
in renal proximal tubule cells where it mediates
luminal secretion of organic cations into the urine,
is expected to impair renal elimination of the cat-
ionic drug metformin. Indeed, after intravenous
administration of metformin, a 4-fold increase in
the AUC of metformin was observed in Mate1 (/)
mice compared to wild-type mice (39). The renal
secretory clearance of metformin in Mate1 (/)
mice was only 14% of that in Mate1 ( / ) mice.
However, Mate1 (/) mice develop a nephropathy
with creatinine clearance declining to only the half
of that in wild-type mice (39). Although this obser-
vation emphasizes the relevance of Mate1 to
normal kidney function, the inherent kidney
dysfunction observed in Mate1 (/) mice obscures
the role of Mate1 in the renal clearance of
metformin.

Figure 1. Localization and functional role of organic cation transporters in the pharmacokinetics of metformin. OCT organic cation
transporter; MATE multidrug and toxin extrusion antiporter; PMAT plasma membrane monoamine transporter. Transporters in
bold-face indicate major routes of metformin disposition in humans.
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
4 O. Zolk
Implication of the polymorphic expression of
OCTs in metformin pharmacokinetics and
pharmacodynamics
Organic cation transporter 1 (OCT1)
Given the importance of OCT1 in metformin uptake
into the liver and thus metformin activity, several
pharmacogenetic studies have focused on polymor-
phisms in the gene encoding OCT1, SLC22A1 , as
modiers of the glycemic response. Human SLC22A1
is a highly polymorphic gene (Table I). Functional
studies in cell-based models have established that
among the naturally occurring protein variants, the
p.61R C, p.189S L, p.220G V, p.401G S,
p.420del, and p.465G R mutants reduce OCT1
function and thus reduce or eliminate metformin
uptake (37). The decrease in uptake by some variant
proteins is probably due to their cytosolic retention
and reduced expression on the plasma membrane,
as was shown for the SLC22A1 p.465G R and
p.61R C variant proteins in transfected cells
(37,40). Recently, Nies et al. conrmed these exper-
imental data in a clinical study by demonstrating that
the presence of the SLC22A1 c.262T C (p.61R C)
SNP in patients strongly correlates with decreased
liver OCT1 protein expression (41). Consistent
with the previously described knock-out studies,
phosphorylation of AMPK following metformin
administration is reduced in cells expressing the
non-functional or reduced-function variants, com-
pared with cells expressing wild-type OCT1. Based
on this experimental observation, it was proposed
that OCT1 mediates the rst step in the response
pathway to metformin and that genetic variation in
SLC22A1 may modulate the response to metformin
in humans.
Shu et al. rst reported that individuals with any
of the four reduced-function alleles (p.61R C,
p.401G S, p.420del, or p.465G R) have a signi-
cantly decreased glucose-lowering response to
metformin compared with reference allele carriers
(Table II summarizes results from clinical studies).
To determine the glycemic response, study partici-
pants (healthy volunteers) underwent oral glucose
tolerance testing before and after two doses of met-
formin. Individuals with the reference sequence
demonstrated a 7% reduction in the area under the
glucose concentration-time curve (glucose AUC),
whereas the glucose-AUC in variant allele carriers
increased from base-line by 8% (Figure 2). Shu et al.
also investigated the effect of SLC22A1 variants on
the pharmacokinetics of metformin in the same
study cohort. Unlike prior animal studies, which
demonstrated no difference in the pharmacokinetic
prole in wild-type or Oct1 (/) mice (26), pharma-
cokinetics differed across the SLC22A1 genotype
groups in humans, with a signicantly higher met-
formin AUC ( 19%), higher maximal plasma concen-
tration (C
max
; 15%), and lower oral volume of
distribution (V/ F ; 47%) in individuals carrying a
reduced-function allele. These effects may be at least
partially explained by a much lower hepatic uptake
of metformin in individuals with a variant allele. Of
note, renal metformin clearance was unchanged
across SLC22A1 genotypes in that study, whereas in
a subsequent study Tzvetkov et al. noted an increase
in renal metformin clearance in healthy volunteers
carrying a SLC22A1 reduced-function allele (42).
Studies in diabetic patients were also conducted
to study pharmacodynamics. Zhou et al. investigated
whether the two most common reduced-function
SNPs in SLC22A1 , p.61R C and p.420del, decrease
the glycemic response in patients with type 2 diabe-
tes (43). In that study, a series of drug response mod-
els for metformin were assessed, including short- and
mid-term HbA
1C
reduction, reaching the treatment
target of HbA
1C
of 7%, and time to monotherapy
failure, in a large population-based study of 1,531
patients recruited to GoDARTS (Genetics of Diabe-
tes Audit and Research Tayside). The study result
was essentially negative, i.e. the SLC22A1 variants
p.61R C and p.420del did not affect the initial
HbA
1C
reduction, the chance of achieving a treat-
ment target, the average HbA
1C
on monotherapy up
to 42 months, or the hazard of monotherapy failure
(43). In another study, Shikata et al. analyzed vari-
ants of SLC22A1 and SLC22A2 in 33 Japanese dia-
betic patients with variable treatment efcacy to
metformin (44). None of the identied polymor-
phisms in either gene was associated with metformin
responder status, which was dened by an absolute
reduction of 0.5% in HbA
1C
within the rst 3
months of metformin therapy. However, when clini-
cal variables were included and multivariate statistics
were applied, two SNPs in SLC22A1 , c.43T G
and c.1222A G, were negative and positive predic-
tors, respectively, for the metformin responder sta-
tus. The biological basis of these associations remains
somewhat elusive, as the c.1222A G SNP is not
associated with altered metformin transport in cel-
lular models, and expression studies in human liver
tissue samples did not reveal any allelic differences
in OCT1 expression. Becker et al. analyzed associa-
tions between 11 tagging SNPs in SLC22A1 and
changes in the HbA
1C
level in a subcohort of 102
incident metformin users from the population-based
Rotterdam study (45). No signicant associations
were observed except for the intronic rs622342 A C
SNP. For each minor C allele of this variant, the
reduction in HbA
1C
levels in diabetic patients was
0.28% less. However, the mechanism by which this
SNP, which is not in linkage disequilibrium with
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
Metformin disposition: role of transporter polymorphisms 5
known reduced-function SLC22A1 SNPs or associ-
ated with renal metformin clearance (42), affects the
glycemic response to metformin remains unclear.
Similar to patients with type 2 diabetes, great
variability in the clinical response to metformin has
also been observed in women with PCOS. To test
whether SNPs in SLC22A1 contribute to the
variability in treatment response, Gambineri et al.
conducted a prospective study in 150 patients of
European descent with PCOS who were treated with
metformin for 6 months (46). Carriers of at least one
of the four SLC22A1 reduced-function alleles
Table I. Polymorphisms investigated in clinical studies, their impact on the in-vitr o transport function, and their allele frequency in different
ethnic populations.
Nucleotide
change
Amino acid
change
Activity
(37,47,62)
European
(ethnic subpopulation,
number of tested
individuals)
(40,41)
African
(ethnic subpopulation,
number of tested
individuals)
(40)
Asian
(ethnic subpopulation,
number of tested
individuals)
(40,47,63)
SLC22A1 (OCT1)
c.262T C p.61R C 0.10 (EC 150)
0.07 (EA 200)
0 (AA 200) 0 (AS 60)
0 (JA 116)
c.289C A p.97Q K 0.02 (JA/HC 59)
c.350C T p.117P L 0.02 (JA 66)
c.616C T p.206R C 0.01 (JA 66)
c.659G T p.220G V 0 (EA 200) 0.01 (AA 200) 0 (AS 60)
c.848C T p.283P L
c.859C G p.287R G
c.1201G A p.401G S 0.01 (EC 150)
0.01 (EA 200)
0.01 (AA 200) 0 (AS 60)
0 (JA 116)
c.1222A G p.408M V 0.60 (EA 200) 0.74 (AA 200) 0.76 (AS 60)
c.1256delATG p.420del 0.17 (EC 150)
0.19 (EA 200)
0.03 (AA 200) 0 (AS 60)
0 (JA 116)
c.1393G A p.465G R 0.04 (EC 150)
0.04 (EA 200)
0 (AA 200) 0 (AS 60)
0 (JA 116)
Nucleotide
change
Amino acid
change
Activity
(50 52)
European
(50,51)
African
(50)
Asian
(50,51,64,65)
SLC22A2 (OCT2)
c.495G A p.165M I 0 (EA 200) 0.01 (AA 200) 0 (AS 60)
c.596C T p.199T I 0 (EC 100) 0 (HC 100)
0.01 (KA 150)
0 (VA 100)
c.602C T p.201T M 0 (EC 100) 0 (HC 100)
0.01 (KA 150)
0.02 (VA 100)
c.808G T p.270A S ( ) 0.16 (EA 200) 0.11 (AA 200) 0.13 (HC 400)
0.14 (HC 100)
0.17 (JA 116)
0.09 (AS 60)
c.1198C T p.400R C 0 (EA 200) 0.02 (AA 200) 0 (JA 116)
0 (AS 60)
c.1294A C p.432K Q 0 (EA 200) 0.01 (AA 200) 0 (JA 116)
0 (AS 60)
Nucleotide
change
Amino acid
change
Activity
(54,55)
European
(54,55)
African
(54,55)
Asian
(54,55)
SLC47A1 (MATE1)
g.66T C / (promoter) 0.32 (EA 68) 0.45 (AA 68) 0.23 (CA 68)
c.404T C p.159T M 0 (EC 253) 0 (AA 95)
0 (TA 95)
0.01 (JA 95)
c.1012G A p.338V I 0 (EC 253) 0.05 (AA 95)
0.10 (TA 95)
0.01 (JA 95)
AA African American; AS Asian American; CA Chinese American; EA European American; EC European Caucasian;
HC Han Chinese; JA Japanese Asian; KA Korean Asian; TA Tanzanian African; VA Vietnamese Asian; reduced transport
function; increased transport function; no change.
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
6 O. Zolk
(p.61R C, p.401G S, p.420del, or p.465G R) had
a signicantly decreased cholesterol- and triglycer-
ide-lowering response to metformin compared with
reference allele carriers. Glucose tolerance testing at
base-line and at the end of the treatment revealed
that the SLC22A1 genotype is a determinant of the
insulin response to metformin, but not of the glucose
AUC. Given that the lipid-lowering effect is one
Table II. Published pharmacogenetic studies investigating associations between polymorphisms in cation transporter genes and transporter
expression, metformin pharmacokinetics, or glycemic effects of metformin therapy.
Study population Outcome (versus reference)
Healthy volunteers: carriers of at least one
reduced-function SLC22A1 allele (p.61R C,
p.401G S, p.420del, or p.465G R) ( n 12)
versusreference allele carriers ( n 8)
Metformin kinetics (at least one
reduced-function allele versus ref.):
AUC ( 19%) C
max
( 15%) CL/ F
( 38%) V/ F ( 47%) CL
R

(66)
Healthy male volunteers ( n 103): association of
SNPs in SLC22A1 , SLC22A2 , SLC22A4 , and
SLC47A1 with metformin renal clearance
Presence of SLC22A1 reduced-function alleles
was associated with increased renal metformin
clearance
(42)
Healthy volunteers: SL22A2 p.270A S
heterozygous ( n 5) and p.270A S homozygous
( n 4)versusreference allele carriers ( n 6)
Metformin kinetics (808 TT versus ref.):
AUC C
max
CL
R
( 26%) In the
presence of cimetidine, metformin CL was
decreased in all participants, but the decrease
was lower in TT than GG carriers
(67)
Healthy volunteers: SLC22A2 p.199T I
heterozygous ( n 3), p.201T M heterozygous
( n 2), p.270A S heterozygous ( n 6), and
p.270A S homozygous ( n 6)versus reference
allele carriers ( n 9)
Metformin kinetics (p.270 SS versus ref.):
AUC ( 73%) C
max
( 63%) CL/ F
( 32%) CL
R
( 51%) In heterozygous allele
carriers, only minor (p.270A S) or no
(p.199T I , p.201T M) changes were seen
(53)
Diabetic patients: heterozygous carriers of variant
SLC47A1 (p.64G D, p.125L F, p.328D A)
and SLC47A2 (p.211G V) alleles ( n 7) versus
reference allele carriers ( n 41)
Metformin kinetics: CL/ F (57)
Tissue samples from human livers; heterozygous
carriers of the SLC22A1 p.61R C allele ( n 29)
versus reference allele carriers ( n 118)
SLC22A1 mRNA expression (41)
Human kidney tissue samples from donors with at
least one SLC47A1 g.66T C variant allele
( n 26) versus samples from donors with the
reference genotype ( n 12)
SLC47A1 mRNA expression ( 34%) (54)
Healthy volunteers: carriers of at least one
reduced-function SLC22A1 allele (p.61R C,
p.401G S, p.420del, or p.465G R) ( n 12)
versus reference allele carriers ( n 8)
Oral glucose (75 g) tolerance test before
and after two doses of metformin: Effect of
metformin on glucose AUC
(37)
Women with PCOS: carriers of at least one
reduced-function SLC22A1 allele (p.61R C,
p.401G S, p.420del, or p.465G R) ( n 66)
versus reference allele carrier ( n 84)
Oral glucose (75 g) tolerance test: Effect
of metformin on glucose AUC after 6 months
of treatment Effect of metformin on insulin
AUC after 6 months of treatment
( 2 variant alleles versus control)
(46)
Patients with diabetes mellitus ( n 1,531):
SLC22A1 p.61R C and p.420del variant allele
carriers versus reference allele carriers
Variants did not affect the initial HbA
1C

reduction, the chance of achieving a treatment
target, the average HbA
1C
on monotherapy up
to 42 months, or the hazard of monotherapy
failure
(43)
Diabetic patients: responders to metformin ( n 24)
versus non-responders ( n 9); correlation of
SLC22A1 and SLC22A2 polymorphisms
(identied by screening the respective genes)
with response to metformin
c.43T G and c.1222A G were negative and
positive predictors, respectively, for the efcacy
of metformin (OCT1 mRNA levels tended to
be lower in human livers with the c.1222A G
variant allele)
(44)
Diabetic patients: association of SNPs in SLC47A1
with reduction in HbA
1C
level after initiation of
metformin treatment in a population-based
cohort ( n 116)
Among genotypes, the intronic SNP rs2289669
(c.922158G A) was signicantly associated
with an increased glucose-lowering effect
(56)
Diabetic patients: association of SNPs in SLC22A1
with reduction in HbA
1C
level after initiation of
metformin treatment in a population-based
cohort ( n 102)
Among genotypes, the SNP rs622342 was
signicantly associated with an increased
glucose-lowering effect
(45)
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
Metformin disposition: role of transporter polymorphisms 7
aspect of the hepatic action of metformin and that
OCT1 plays a trigger role in hepatic metformin uptake,
this observation is in agreement with the hypothesis
that polymorphisms in SLC22A1 contribute to the
variable response to metformin.
The genotypic frequencies of the non-synonymous,
reduced-function polymorphisms in SLC22A1 vary
substantially among different races or ethnicities. In
general, they are rare in Asian populations and most
frequent in Caucasians (Table I). Although this
observation may be biased because genetic variants
in SLC22A1 have been investigated and identied
largely in European populations, a recent screen for
genetic variants in SLC22A1 in Chinese and Japa-
nese populations did not substantially change the
conclusion (47). Given the important role of OCT1
in hepatic uptake and action of metformin, inter-
ethnic differences in the frequency of SLC22A1
reduced-function SNPs may be associated with
inter-ethnic differences in the pharmacodynamic
prole of metformin (48). Signicant heterogeneity
in metformin efcacy by ethnic group, however, was
not observed (49).
Organic cation transporter 2 (OCT2)
Given the importance of OCT2 in metformin phar-
macokinetic disposition, some pharmacogenetic
studies have focused on polymorphisms in the gene
encoding OCT2, SLC22A2 , as a modier of met-
formin renal clearance. To date, almost 500 variable
sites in SLC22A2 have been identied. Thirteen
cause non-synonymous amino acid changes, and
most are present at frequencies of less than 1%.
Some variants such as p.165M I, p.199T I,
p.201T M, and p.400R C lead to clearly reduced
activity compared to the OCT2 reference (50,51),
whereas the p.270A S (c.808G T) variant has
more subtle effects on transporter function in vitro
(52). Most pharmacogenetic studies performed in
healthy volunteers have focused on the last-men-
tioned SNP because it is the only common coding
polymorphism in SLC22A2 , with an allele frequency
of about 15% regardless of the ethnic background.
Overall, these studies suggest that the SLC22A2
c.808G T SNP has no signicant impact on renal
metformin clearance in heterozygous carriers (Fig-
ure 3). A marked reduction in metformin clearance
by almost 40%, however, was observed in volunteers
with the homozygous variant TT genotype. For this
polymorphism, the results obtained so far (Figure 3)
t well with a recessive model of genotype pheno-
type interaction, i.e. changes in renal metformin
clearance occur only when both c.808 alleles are dys-
functional. Thus, it is possible that patients with the
SLC22A2 c.808 GG or GT genotype will require a
different dosage of metformin to achieve optimal
glucose control compared with homozygous TT
allele carriers. However, data are lacking to show
whether SLC22A2 c.808G T genotype-dependent
changes in metformin pharmacokinetics (demon-
strated only in healthy volunteers so far) translate
into changes in metformin glycemic response in
patients.
Song et al. identied few heterozygous carriers of
the rare SLC22A2 c.596C T (p.199T I) and
c.602C T (p.201T M) variants (which exhibit
reduced transport of metformin in cellular assays) and
compared metformin clearance in these individuals
with that in wild-type allele carriers (53). These stud-
ies suggest that the presence of one reduced-function
SLC22A2 c.596C T or c.602C T allele leads to a
reduction in renal metformin clearance comparable
to that observed in homozygous SLC22A2 c.808 TT
carriers. The small number of tested individuals, how-
ever, precludes denite conclusions. Because these
SNPs occur only in some ethnic subpopulations and
at a frequency of 1%, their clinical impact in view
of a population-based pharmacogenetic screening
approach is rather limited.
Multidrug and toxin extrusion antiporters
(MATE1, MATE2)
As described above, the MATE1 and MATE2 trans-
porters, which are located in the canalicular mem-
brane of hepatocytes and in the brush border of the

Figure 2. Association of SLC22A1 (OCT1) variants with response
to metformin in healthy volunteers. Oral glucose (75 g) tolerance
test was performed before (base-line) and after two doses of
metformin. The glucose AUC was calculated from the time
course of plasma glucose concentrations. Comparison of healthy
individuals with only reference SLC22A1 alleles ( n 8) and
those with at least one reduced-function allele in SLC22A1 :
p.61R C, p.401G S, p.420del, or p.465G R ( n 12). Data
are from (37).
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
8 O. Zolk
renal epithelium, are responsible for the nal step of
the excretion of cationic compounds into bile and
urine, respectively. Metformin is a substrate of these
transporters, and therefore these transporters may
be involved in metformin excretion. Several poly-
morphisms have been identied and characterized
in the gene encoding MATE1, SLC47A1 . SLC47A1
mRNA expression, for example, is signicantly
lower in human kidney samples from individuals
who are homozygous or heterozygous for the
SLC47A1 g.66T C SNP in the basal promoter in
comparison with samples from homozygous refer-
ence allele carriers (54). In-vitro experiments sug-
gest that the reduced transcriptional activity of
SLC47A1 g.66T C results from a reduction in the
binding potency of the transcriptional activator,
activating protein-1, and an enhanced binding
potency of the repressor, activating protein-2 repres-
sor, to the mutant basal promoter region (54). In
cellular models, two non-synonymous SNPs in
SLC47A1 , p.159T M (c.404T C) and p.338V A
(c.1012G A), cause a signicant loss in transporter
activity for metformin (55). Unfortunately, no stud-
ies have been reported that examine the effect of the
experimentally characterized promoter or reduced-
function variants on the pharmacokinetics and
pharmacodynamics of metformin in patients.
Based on data from the population-based Rot-
terdam cohort study, a signicant association between
the tagging rs2289669 G A SNP in SLC47A1 and
metformin response in a study sample of 116 inci-
dent metformin users was observed (56). The SNP
was associated with an increased glucose-lowering
effect. For each minor A allele, the HbA
1C
reduction
was 0.3% larger (56). However, the small sample size,
the limited clinical phenotype, and the lack of a rep-
lication study limit the informative value of this study.
In another clinical study, Toyama et al. observed no
differences in metformin disposition (evaluated by
recording the plasma concentration time prole after
oral administration of metformin) between diabetic
patients carrying a heterozygous variation in SLC47A1
or SLC47A2 and patients with the reference genotype
(57). Similarly, no differences were observed in met-
formin pharmacokinetics between heterozygous
Mate1 ( /) knock-out mice and Mate1 ( / ) wild-
type mice, whereas metformin kinetics were mark-
edly affected in homozygous Mate1 (/) knock-out
mice. Thus, the authors hypothesized that heterozy-
gous variants in SLC47A1 and SLC47A2 do not sub-
stantially contribute to the interindividual variation
in metformin pharmacokinetics (57). The postulated
recessive model of the SLC47A1/2 genotype pheno-
type interaction seems to be plausible particularly
because two MATE efux transporters with substrate
redundancies are expressed, such that one MATE
transporter can compensate at least partially for an
inherently reduced expression or function of another
MATE transporter.
Conclusion
Several non-synonymous, promoter and deletion-
type variants in the SLC22A1 , SLC22A2 , and

Figure 3. Effects of polymorphisms in genes encoding the organic cation transporter 2 (OCT2, SLC22A2 ) on renal clearance (CL
R
) of
metformin in healthy volunteers. Synopsis/meta-analysis (analysis method: xed effect inverse variance model) of published studies
(42,53,67,68). Modied from (69).
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
Metformin disposition: role of transporter polymorphisms 9
SLC47A1 organic transporter genes exhibit reduced
transporter activity of metformin in experimental
studies. The best-studied SNP in humans with
respect to the pharmacokinetics of metformin is the
SLC22A2 p.270A S SNP, which shows a recessive
mode of genotype phenotype interaction with an
almost 40% reduction in renal metformin clearance
in homozygous carriers of the minor allele. At the
level of pharmacokinetics in healthy individuals, the
results are less controversial; however, the results are
inconsistent when focusing on the glycemic response
to metformin in patients with type 2 diabetes. In
clinical studies, metformin has a decreased effect on
glucose tolerance in healthy individuals who carry
reduced-function polymorphisms of SLC22A1 .
However, these ndings were not conrmed in a ret-
rospective study of 1,531 metformin-treated diabetic
patients, which showed no differential effect in
HbA
1C
reduction when considering the two most
frequent index variants at this locus.
Why have we so far failed to establish genotypes
of organic cation transporter genes ( SLC22A1 ,
SLC22A2 , SLC47A1 , SLC47A2 ) as validated predic-
tors of pharmacokinetics and clinical response
to metformin in patients? Possibly, the effects of
single genetic polymorphisms in transporter genes
are too small against a noisy background caused by
environmental factors, age, gender, and co-morbid-
ities. In fact, in a study of young female patients
with PCOS who presumably had few co-morbidities
(i.e. with more tight control of non-genetic covari-
ates), the SLC22A1 genotype was found to be a sig-
nicant determinant of lipid and insulin responses
to metformin (46).
Estimates of the contribution of genes and envi-
ronment to the variation in renal metformin clear-
ance suggest a strong genetic inuence in Caucasian
and Asian populations (genetic component r
GC
0.9)
(28,29). However, caution is needed in interpreta-
tion of these data obtained from two small popula-
tions of young healthy subjects. Both studies clearly
failed to reach satisfactory statistical power (58).
Moreover, the value of heritability applies only to
the population in which it was established. Assum-
ing a given extent of genetic control, the heritability
of renal clearance of metformin tends to be larger
the more uniform the tested population. Although
the exact value is not known, an r
GC
value 0.9
certainly under-estimates the environmental com-
ponent of renal metformin clearance in a general
population, as indicated by calculations of Tzvetkov
et al. Considering only the two non-genetic param-
eters kidney function and age, these parameters are
explaining 42% and 9% of the variation in renal
clearance of metformin, respectively (42). Three
decades ago, Sirtori et al. and Tucker et al. observed
that renal metformin clearance is highly correlated
with creatinine clearance (20,27). Cholestasis was
also identied as an important non-genetic factor
that is associated with markedly reduced OCT
mRNA and protein expression in the human liver
(41), potentially affecting hepatic disposition of
metformin.
Moreover, variations in genes other than those
encoding OCTs and MATEs are likely to modulate
the pharmacokinetics or response to metformin ther-
apy. For example, some recent studies suggest a role
for STK11 , a molecular target gene of metformin, in
the treatment response to metformin (59,60).
Another candidate is SLC29A4 , which encodes the
plasma membrane monoamine transporter (PMAT).
PMAT transports metformin, is expressed in human
intestine, and may play a role in the intestinal absorp-
tion of metformin (61). Unlike warfarin in which
40% of the variation in treatment response is due to
two genes, VCORCI and CYP2C9 , the pharmacoge-
netics of metformin seems to not be one of the few
cases in which one or a few genes determines a large
proportion of the variation of the response to a drug.
One reason for the polygenic phenotype of met-
formin pharmacokinetics may be the functional
redundancy of some human transporters. Metformin
is a substrate of human MATE1 and MATE2 trans-
porters, which are expressed at the renal brush bor-
der membrane. Another example is OCT1 and
OCT3, which are localized at the basolateral hepa-
tocyte membrane (41). Although OCT3 is expressed
in the human liver at lower levels than OCT1, OCT3
transports metformin with a higher efcacy than
OCT1 and thus may counterbalance impaired OCT1
function (41).
In conclusion, investigation of polymorphisms
in organic cation transporters and attempts to link
the variants with the pharmacokinetics and phar-
macodynamics of metformin have provided valu-
able information about the role of these
transporters in the disposition of metformin in
humans. Knowing the biology of the polymor-
phisms in genes dening the disposition of met-
formin (a prototypic cationic drug) may bring us
a step closer to clinical application in terms of
individualized drug therapy.
Acknowledgements
I thank MF Fromm for critical reading of the
manuscript.
Declaration of interest: The author states no
conict of interest and has received no payment in
preparation of this manuscript.
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
10 O. Zolk
References
1. Consensus on infertility treatment related to polycystic ovary
syndrome. Hum Reprod. 2008;23:462 77.
Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin 2.
compared with glyburide in gestational diabetes: a rand-
omized controlled trial. Obstet Gynecol. 2010;115:55 9.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, 3.
et al. Role of AMP-activated protein kinase in mechanism of
metformin action. J Clin Invest. 2001;108:1167 74.
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, 4.
Depinho RA, et al. The kinase LKB1 mediates glucose
homeostasis in liver and therapeutic effects of metformin.
Science. 2005;310:1642 6.
Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, 5.
Mithieux G, et al. Metformin inhibits hepatic gluconeogen-
esis in mice independently of the LKB1/AMPK pathway via
a decrease in hepatic energy state. J Clin Invest. 2010;
120:2355 69.
Effect of intensive blood-glucose control with metformin on 6.
complications in overweight patients with type 2 diabetes
(UKPDS 34). UK Prospective Diabetes Study (UKPDS)
Group. Lancet. 1998;352:854 65.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 7.
10-year follow-up of intensive glucose control in type 2 dia-
betes. N Engl J Med. 2008;359:1577 89.
Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque 8.
M, Moher D. Metformin monotherapy for type 2 diabetes
mellitus. Cochrane Database Syst Rev. 2005;2005(3):
CD002966.
IMS Health. IMS National Prescription Audit. 2010. http:// 9.
www.imshealth.com/deployedfiles/imshealth/Global/Con-
tent/StaticFile/Top_Line_Data/Top%2015%20Prod-
ucts%20by%20U%20S%20RXs.pdf.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes 10.
mellitus. Ann Intern Med. 1999;131(4):281 303.
Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, 11.
Fleming GA. Lactic acidosis in patients with diabetes treated
with metformin. N Engl J Med. 1998;338:265 6.
Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of 12.
fatal and nonfatal lactic acidosis with metformin use in type
2 diabetes mellitus. Cochrane Database Syst Rev. 2010;
(4):CD002967.
FDA drug label, metformin hydrochloride tablets (Glu- 13.
cophage). 2008. http://www.accessdata.fda.gov/drugsatfda_
docs/label/2008/020357s031,021202s016lbl.pdf.
Zolk O, Solbach TF, Konig J, Fromm MF. Structural deter- 14.
minants of inhibitor interaction with the human organic
cation transporter OCT2 (SLC22A2). Naunyn Schmiede-
bergs Arch Pharmacol. 2009;379:337 48.
Inzucchi SE. Oral antihyperglycemic therapy for type 2 15.
diabetes: scientic review. JAMA. 2002;287:360 72.
Hermann LS, Schersten B, Bitzen PO, Kjellstrom T, Lind- 16.
garde F, Melander A. Therapeutic comparison of metformin
and sulfonylurea, alone and in various combinations. A dou-
ble-blind controlled study. Diabetes Care. 1994;17:1100 9.
Kahn SE, Haffner SM, Heise MA, Herman WH, Holman 17.
RR, Jones NP, et al. Glycemic durability of rosiglitazone,
metformin, or glyburide monotherapy. N Engl J Med.
2006;355:2427 43.
Pearson ER, Donnelly LA, Kimber C, Whitley A, Doney AS, 18.
McCarthy MI, et al. Variation in TCF7L2 inuences thera-
peutic response to sulfonylureas: a GoDARTs study. Diabe-
tes. 2007;56:2178 82.
Pacanowski MA, Hopley CW, Aquilante CL. Interindividual 19.
variability in oral antidiabetic drug disposition and response:
the role of drug transporter polymorphisms. Expert Opin
Drug Metab Toxicol. 2008;4:529 44.
Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods 20.
HF. Metformin kinetics in healthy subjects and in patients with
diabetes mellitus. Br J Clin Pharmacol. 1981;12:235 46.
Pentikainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics 21.
of metformin after intravenous and oral administration to
man. Eur J Clin Pharmacol. 1979;16:195 202.
Sambol NC, Chiang J, O Conner M, Liu CY, Lin ET, 22.
Goodman AM, et al. Pharmacokinetics and pharmacody-
namics of metformin in healthy subjects and patients with
noninsulin-dependent diabetes mellitus. J Clin Pharmacol.
1996;36:1012 21.
Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymor- 23.
phism in human organic cation transporters and metformin
action. Pharmacogenomics. 2008;9:415 22.
Proctor WR, Bourdet DL, Thakker DR. Mechanisms under- 24.
lying saturable intestinal absorption of metformin. Drug
Metab Dispos. 2008;36:1650 8.
Wilcock C, Bailey CJ. Accumulation of metformin by tissues 25.
of the normal and diabetic mouse. Xenobiotica. 1994;24:
49 57.
Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, 26.
Sugiyama Y. Involvement of organic cation transporter 1 in
hepatic and intestinal distribution of metformin. J Pharma-
col Exp Ther. 2002;302:510 5.
Sirtori CR, Franceschini G, Galli-Kienle M, Cighetti G, 27.
Galli G, Bondioli A, et al. Disposition of metformin (N,
N-dimethylbiguanide) in man. Clin Pharmacol Ther.
1978;24:683 93.
Yin OQ, Tomlinson B, Chow MS. Variability in renal clear- 28.
ance of substrates for renal transporters in chinese subjects.
J Clin Pharmacol. 2006;46:157 63.
Leabman MK, Giacomini KM. Estimating the contribution 29.
of genes and environment to variation in renal drug clear-
ance. Pharmacogenetics. 2003;13:581 4.
Zhang L, Dresser MJ, Gray AT, Yost SC, Terashita S, Giaco- 30.
mini KM. Cloning and functional expression of a human liver
organic cation transporter. Mol Pharmacol. 1997;51:913 21.
Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer- 31.
Teuber I, Karbach U, Quester S, et al. Cloning and charac-
terization of two human polyspecic organic cation
transporters. DNA Cell Biol. 1997;16:871 81.
Kimura N, Okuda M, Inui K. Metformin transport by renal 32.
basolateral organic cation transporter hOCT2. Pharm Res.
2005;22:255 9.
Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, 33.
Katsura T, et al. Identication and functional characteriza-
tion of a new human kidney-specic H /organic cation
antiporter, kidney-specic multidrug and toxin extrusion 2.
J Am Soc Nephrol. 2006;17:2127 35.
Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, 34.
Moriyama Y. A human transporter protein that mediates the
nal excretion step for toxic organic cations. Proc Natl Acad
Sci U S A. 2005;102:17923 8.
Jonker JW, Wagenaar E, Van ES, Schinkel AH. Deciency in 35.
the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/
Slc22a2]) in mice abolishes renal secretion of organic cati-
ons. Mol Cell Biol. 2003;23:7902 8.
Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, 36.
Smit JW, et al. Reduced hepatic uptake and intestinal excre-
tion of organic cations in mice with a targeted disruption of
the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol
Cell Biol. 2001;21:5471 7.
Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro 37.
RA, et al. Effect of genetic variation in the organic cation
transporter 1 (OCT1) on metformin action. J Clin Invest.
2007;117:1422 31.
Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, 38.
Sugiyama Y. Involvement of organic cation transporter 1 in
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.
Metformin disposition: role of transporter polymorphisms 11
the lactic acidosis caused by metformin. Mol Pharmacol.
2003;63:844 8.
Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, Inui 39.
K. Targeted disruption of the multidrug and toxin extrusion
1 (mate1) gene in mice reduces renal secretion of metformin.
Mol Pharmacol. 2009;75:1280 6.
Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, 40.
Stryke D, et al. Evolutionary conservation predicts function
of variants of the human organic cation transporter, OCT1.
Proc Natl Acad Sci U S A. 2003;100:5902 7.
Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, 41.
et al. Expression of organic cation transporters OCT1
(SLC22A1) and OCT3 (SLC22A3) is affected by genetic
factors and cholestasis in human liver. Hepatology. 2009;50:
1227 40.
Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt 42.
T, Sehrt D, et al. The effects of genetic polymorphisms in
the organic cation transporters OCT1, OCT2, and OCT3
on the renal clearance of metformin. Clin Pharmacol Ther.
2009;86:299 306.
Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, 43.
Leese G, et al. Reduced-function SLC22A1 polymorphisms
encoding organic cation transporter 1 and glycemic response
to metformin: a GoDARTS study. Diabetes. 2009;58:1434 9.
Shikata E, Yamamoto R, Takane H, Shigemasa C, Ikeda T, 44.
Otsubo K, et al. Human organic cation transporter (OCT1
and OCT2) gene polymorphisms and therapeutic effects of
metformin. J Hum Genet. 2007;52:117 22.
Becker ML, Visser LE, van Schaik RH, Hofman A, Uitter- 45.
linden AG, Stricker BH. Genetic variation in the organic
cation transporter 1 is associated with metformin response in
patients with diabetes mellitus. Pharmacogenomics J. 2009;
9:242 7.
Gambineri A, Tomassoni F, Gasparini DI, Di Rocco A, Man- 46.
tovani V, Pagotto U, et al. Organic cation transporter 1
polymorphisms predict the metabolic response to metformin
in women with the polycystic ovary syndrome. J Clin Endo-
crinol Metab. 2010;95:E204 8.
Chen L, Takizawa M, Chen E, Schlessinger A, Choi JH, 47.
Segenthelar J, et al. Genetic polymorphisms in the organic
cation transporter 1, OCT1, in Chinese and Japanese popu-
lations, exhibit altered function. J Pharmacol Exp Ther.
2010;335:42 50.
Ieiri I, Higuchi S. [Pharmacogenomics: inter-ethnic and 48.
intra-ethnic differences in pharmacokinetic and pharmaco-
dynamic proles of clinically relevant drugs]. Yakugaku
Zasshi. 2009;129:231 5.
Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, 49.
Marcovina S, et al. The effect of metformin and intensive
lifestyle intervention on the metabolic syndrome: the Diabe-
tes Prevention Program randomized trial. Ann Intern Med.
2005;142:611 9.
Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke 50.
D, Ferrin TE, et al. Polymorphisms in a human kidney xeno-
biotic transporter, OCT2, exhibit altered function. Pharma-
cogenetics. 2002;12:395 405.
Kang HJ, Song IS, Shin HJ, Kim WY, Lee CH, Shim JC, et 51.
al. Identication and functional characterization of genetic
variants of human organic cation transporters in a Korean
population. Drug Metab Dispos. 2007;35:667 75.
Zolk O, Solbach TF, K nig J, Fromm MF. Functional 52.
characterization of the human organic cation transporter 2
variant p.270Ala Ser. Drug Metab Dispos. 2009;37:1312 8.
Song IS, Shin HJ, Shim EJ, Jung IS, Kim WY, Shon JH, 53.
et al. Genetic variants of the organic cation transporter
2 inuence the disposition of metformin. Clin Pharmacol
Ther. 2008;84:559 62.
Ha CJ, Wah YS, Kim MJ, Nguyen L, Ho LJ, Kang JO, et al. 54.
Identication and characterization of novel polymorphisms
in the basal promoter of the human transporter, MATE1.
Pharmacogenet Genomics. 2009;19:770 80.
Meyer zu Schwabedissen HE, Verstuyft C, Kroemer HK, Bec- 55.
quemont L, Kim RB. Human multidrug and toxin extrusion
1 (MATE1/SLC47A1) transporter: functional characteriza-
tion, interaction with OCT2 (SLC22A2), and single nucle-
otide polymorphisms. Am J Physiol Renal Physiol. 2010;
298:F997 1005.
Becker ML, Visser LE, van Schaik RH, Hofman A, Uitter- 56.
linden AG, Stricker BH. Genetic variation in the multidrug
and toxin extrusion 1 transporter protein inuences the
glucose-lowering effect of metformin in patients with diabe-
tes: a preliminary study. Diabetes. 2009;58:745 9.
Toyama K, Yonezawa A, Tsuda M, Masuda S, Yano I, Terada 57.
T, et al. Heterozygous variants of multidrug and toxin extru-
sions (MATE1 and MATE2-K) have little inuence on the
disposition of metformin in diabetic patients. Pharmaco-
genet Genomics. 2010;20:135 8.
Kalow W, Endrenyi L, Tang B. Repeat administration of 58.
drugs as a means to assess the genetic component in phar-
macological variability. Pharmacology. 1999;58:281 4.
Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, 59.
Carson SA, et al. Ovulatory response to treatment of polycystic
ovary syndrome is associated with a polymorphism in the
STK11 gene. J Clin Endocrinol Metab. 2008;93:792 800.
Lopez-Bermejo A, Diaz M, Moran E, de Zegher F, Ibanez L. 60.
A single nucleotide polymorphism in STK11 inuences insu-
lin sensitivity and metformin efcacy in hyperinsulinemic
girls with androgen excess. Diabetes Care. 2010;33:1544 8.
Zhou M, Xia L, Wang J. Metformin transport by a newly 61.
cloned proton-stimulated organic cation transporter (plasma
membrane monoamine transporter) expressed in human
intestine. Drug Metab Dispos. 2007;35:1956 62.
Sakata T, Anzai N, Shin HJ, Noshiro R, Hirata T, Yokoyama 62.
H, et al. Novel single nucleotide polymorphisms of organic
cation transporter 1 (SLC22A1) affecting transport func-
tions. Biochem Biophys Res Commun. 2004;313:789 93.
Itoda M, Saito Y, Maekawa K, Hichiya H, Komamura K, 63.
Kamakura S, et al. Seven novel single nucleotide polymor-
phisms in the human SLC22A1 gene encoding organic
cation transporter 1 (OCT1). Drug Metab Pharmacokinet.
2004;19:308 12.
Li Q, Liu F, Zheng TS, Tang JL, Lu HJ, Jia WP. SLC22A2 64.
gene 808 G/T variant is related to plasma lactate concentra-
tion in Chinese type 2 diabetics treated with metformin. Acta
Pharmacol Sin. 2010;31:184 90.
Fukushima-Uesaka H, Maekawa K, Ozawa S, Komamura 65.
K, Ueno K, Shibakawa M, et al. Fourteen novel single nucle-
otide polymorphisms in the SLC22A2 gene encoding human
organic cation transporter (OCT2). Drug Metab Pharma-
cokinet. 2004;19:239 44.
Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, 66.
et al. Effect of genetic variation in the organic cation trans-
porter 1, OCT1, on metformin pharmacokinetics. Clin
Pharmacol Ther. 2008;83:273 80.
Wang ZJ, Yin OQ, Tomlinson B, Chow MS. OCT2 polymor- 67.
phisms and in-vivo renal functional consequence: studies
with metformin and cimetidine. Pharmacogenet Genomics.
2008;18:637 45.
Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman 68.
MK, et al. Effect of genetic variation in the organic cation
transporter 2 on the renal elimination of metformin. Phar-
macogenet Genomics. 2009;19:497 504.
Zolk O. Current understanding of the pharmacogenomics of 69.
metformin. Clin Pharmacol Ther. 2009;86:595 8.
A
n
n

M
e
d

D
o
w
n
l
o
a
d
e
d

f
r
o
m

i
n
f
o
r
m
a
h
e
a
l
t
h
c
a
r
e
.
c
o
m

b
y

U
n
i
v
e
r
s
i
t
a
e
t
s
b
i
b
l
i
o
t
h
e
k

E
r
l
a
n
g
e
n
-
N
u
e
r
n
b
e
r
g

o
n

0
3
/
0
3
/
1
1
F
o
r

p
e
r
s
o
n
a
l

u
s
e

o
n
l
y
.