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nature publishing group
Transporter Pharmacogenetics and Statin Toxicity
M Niemi1
Polymorphisms in transporter genes can have profound effects
on statin pharmacokinetics. In particular, a common genetic
variant of organic anion–transporting polypeptide 1B1
reduces the hepatic uptake of many statins, increasing the risk
of statin-induced myopathy. Similarly, genetically impaired
adenosine triphosphate (ATP)-binding cassette G2 transporter
efflux activity results in a marked increase in systemic exposure
to various statins. Importantly, the effects of these genetic
polymorphisms differ depending on the specific statin that is
used. This provides a rational basis for the individualization of
lipid-lowering therapy.
Statins are among the most widely used drugs worldwide. They
are usually very well tolerated, but they can cause myopathy
as a rare, plasma concentration–dependent adverse reaction.1
Symptoms of statin-induced myopathy include fatigue, muscle
pain, muscle tenderness, muscle weakness, and cramping, which
can occur with or without an increase in the blood concentration of creatine kinase. The clinical spectrum of statin-induced
myopathy ranges from a mild and relatively common myalgia
to a life-threatening and rare rhabdomyolysis.
Statins differ considerably in their pharmacokinetic characteristics.1 Simvastatin and lovastatin are administered in an
inactive lactone form and are converted to an active acid form
in the body, whereas other statins (atorvastatin, fluvastatin,
pravastatin, rosuvastatin, pitavastatin) are administered in the
active acid form. The main clearance mechanism for the more
lipophilic statins is oxidative biotransformation, whereas the
more hydrophilic statins (pravastatin, rosuvastatin) are excreted
mainly in the unchanged form. Simvastatin, lovastatin, and
atorvastatin are metabolized primarily through CYP3A4, and
fluvastatin is metabolized mainly through CYP2C9.1 Although
these characteristics are important determinants of many drug–
drug interactions affecting statin pharmacokinetics, all statins
are also substrates of membrane transporters, which have
been shown to play an important role in statin disposition.
Importantly, certain transporters display significant genetic
polymorphism, which affects the pharmacokinetics and ­toxicity
of statins.
Slco1b1 and Statins
SLCO1B1 encodes the organic anion–transporting polypeptide
1B1 (OATP1B1) influx transporter, which is expressed on the
basolateral membrane of human hepatocytes.2 Consequently,
OATP1B1 mediates the hepatic uptake of its substrates from
portal blood. In addition to OATP1B1, two other OATP transporters—OATP1B3 and OATP2B1—are expressed on the hepatocyte basolateral membrane in quantities roughly similar to that
of OATP1B1.3 Two common single-nucleotide polymorphism
(SNP) variants of the SLCO1B1 gene—c.388A>G (p.Asn130Asp;
rs2306283) and c.521T>C (p.Val174Ala; rs4149056)—have
been shown to affect the transport function of OATP1B1.4 The
effects, however, depend on their combination in individual
haplotypes. When the c.388A>G exists without the c.521T>C
SNP, the haplotype is termed SLCO1B1*1B; it is usually associated with increased activity of OATP1B1 and therefore with
lower plasma concentrations of OATP1B1 substrates.5,6 The
c.521T>C SNP reduces the transport activity of OATP1B1 and
increases the plasma concentrations of OATP1B1 substrates,
both in the SLCO1B1*5 (c.521T>C alone) haplotype and in the
SLCO1B1*15 (c.521T>C along with c.388A>G) haplotype.7,8 The
low-activity SLCO1B1*5 and *15 haplotypes (i.e., c.521C allele)
have a combined allele frequency of ~15–20% in Caucasians,
10–15% in Asians, and 2% in sub-Saharan Africans and African
Americans.9 The SLCO1B1*1B haplotype has a frequency of
~25–30% in Caucasians, 40% in South/Central Asians, 60%
in East Asians, and 80% in sub-Saharan Africans and African
Americans.9
All statins are substrates of OATP1B1,3,10–15 but the effects
of SLCO1B1 polymorphism differ depending on the specific
statin that is used. The effect is largest on simvastatin; the area
under the plasma concentration–time curve (AUC) of active
simvastatin acid has been shown to be 221% greater in individuals with the c.521CC genotype than in those with the c.521TT
genotype (Figure 1).13 The AUC of pitavastatin was shown to
be 162–191% greater (weighted mean 173%),15–17 that of atorvastatin was 144% greater,18 that of pravastatin was 57–130%
greater (weighted mean 90%),7,8,15,19,20 and that of rosuvastatin
was 62–117% greater (weighted mean 87%)18,21,22 in individuals
1Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Correspondence: M Niemi
([email protected])
Received 3 August 2009; accepted 17 August 2009; advance online publication 4 November 2009. doi:10.1038/clpt.2009.197
130
VOLUME 87 NUMBER 1 | january 2010 | www.nature.com/cpt
prac tice
521T>C
3.5
3
ATG
TAA
2.5
2
1.5
ta
tin
as
ta
tin
with the c.521CC genotype than in those with the c.521TT
­genotype. Individuals with the c.521TC genotype generally
­display modestly increased AUC values that lie between the
­values for individuals with the c.521TT and those for individuals
with the c.521CC genotype.5–8,13,15–22 The SLCO1B1 c.521T>C
SNP has no effect on the pharmacokinetics of fluvastatin.19 The
differences in the effects of SLCO1B1 polymorphism on the
pharmacokinetics of individual statins may be partly explained
by varying contributions of other OATPs to their hepatic uptake.
For example, fluvastatin and rosuvastatin are also substrates of
OATP1B3 and OATP2B1,3,10,14 pravastatin and atorvastatin are
substrates of OATP2B1,23,24 and pitavastatin is a substrate of
OATP1B3.12
The SLCO1B1*1B/*1B genotype has been associated with
a 35% reduction in the AUC of pravastatin relative to the
SLCO1B1*1A/*1A genotype6 but does not seem to affect
the pharmacokinetics of rosuvastatin.21,22 The effects of the
SLCO1B1*1B/*1B genotype on the pharmacokinetics of other
statins are unknown. Although most pharmacokinetic studies
have been single-dose studies, one study that involved multiple doses found that the effects of SLCO1B1 polymorphism on
pravastatin pharmacokinetics are similar after a single dose and
after a 3-week treatment.25
The SLCO1B1 c.521T>C SNP is strongly associated with
simvastatin-induced myopathy (Figure 2).26 Approximately
300,000 genome markers were determined in 85 patients who
had developed myopathy while receiving 80 mg simvastatin daily
and in 90 controls without myopathy.26 A noncoding SNP in the
SLCO1B1 gene, which is in nearly complete linkage disequilibrium with the c.521T>C SNP, was associated with myopathy at a
genome-wide significance level.26 More than 60% of the myopathy cases could be attributed to the c.521T>C SNP, with an
odds ratio of 4.5 per copy of the c.521C allele.26 The association
was seen to be replicated in a study of 20,000 patients receiving
40 mg simvastatin daily, yielding a relative risk of 2.6 per copy of
the c.521C allele.26 Moreover, the c.521T>C SNP was associated
with a slight reduction in the cholesterol-lowering efficacy of
Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 1 | january 2010
7
Simvastatin acid (ng/ml)
Figure 1 Effects of SLCO1B1, ABCG2, and ABCB1 genotypes on the systemic
exposure of various statins. Data are shown as multiples of increase in plasma
area under the plasma concentration–time curve by SLCO1B1 c.521CC, ABCG2
c.421AA, and ABCB1 c.1236TT-c.2677TT-c.3435TT genotype as compared with
the reference genotype (c.521TT, c.421CC, and c.1236CC-c.2677GG-c.3435CC,
respectively). Weighted mean values from various studies are shown for
pitavastatin, rosuvastatin, and pravastatin. References are in the text.
CC
6
5
4
TC
3
2
1
0
TT
0
1 2
3
4 5
7
Time (h)
9
12
20
CC
Cumulative percentage of
patients with myopathy
as
Val174Ala
Fl
uv
uv
as
ta
tin
SLCO1B1
ABCG2
ABCB1
R
os
st
at
in
Pr
av
At
or
va
id
ta
tin
Pi
ta
v
as
ac
la
c
st
at
in
Si
m
va
Si
m
va
st
at
in
to
n
e
1
15
10
5
TC
0
TT
0
1
2
3
4
5
6
Years since starting simvastatin (80 mg/day)
Figure 2 Genetically impaired activity of organic anion–transporting
polypeptide 1B1 reduces the hepatic uptake of active simvastatin acid,
causing accumulation of simvastatin acid in plasma and an increased risk
of myopathy. Simvastatin acid plasma concentration data after a single 40-mg
oral simvastatin dose in healthy volunteers are from ref. 13, reproduced with
permission (Copyright © 2006 Lippincott Williams & Wilkins). The data on
myopathy incidence during 80 mg daily simvastatin therapy are from ref. 26,
reproduced with permission (Copyright © 2008 Massachusetts Medical
Society; all rights reserved).
simvastatin, whereas the c.388A>G SNP was ­associated with a
slightly enhanced efficacy.26 These findings are consistent with
the hypothesis that the c.521T>C SNP is associated with a reduction in hepatic uptake and that the *1B haplotype is associated
with an enhancement in uptake. It is probable that the SLCO1B1
c.521T>C SNP is associated with an increased risk of myopathy
in the case of most other statins as well; however, the risk attributable to the c.521T>C SNP probably depends on the specific
statin that is used.
Abcg2 and Statins
ABCG2 encodes the ATP-binding cassette G2 (ABCG2) efflux
transporter, also known as breast cancer resistance protein.27
ABCG2 is expressed in the apical membranes of intestinal
131
prac tice
SLCO1B1 c.521T>C genotype
TT
TC
CC
20 mg
40 mg
80 mg
Simvastatin
1 mg
2 mg
4 mg
Pitavastatin
20 mg
40 mg
Atorvastatin 80 mg
40 mg
40 mg
80 mg
Pravastatin
20 mg
20 mg
Rosuvastatin 40 mg
80 mg
80 mg
80 mg
Fluvastatin
Normal dose range*
5–80 mg/day
1–4 mg/day
10–80 mg/day
10–80 mg/day
5–40 mg/day
20–80 mg/day
Figure 3 Recommended maximum statin doses for Caucasian adult
patients according to SLCO1B1 genotype. Statin therapy should be started
with the starting dose recommended by the manufacturer or half of the
recommended maximum dose, whichever is lower. The dose should be
titrated up to the minimum effective dose or the suggested maximum
dose on the basis of lipid response and tolerability, and the statin should
be changed or discontinued as necessary. Other factors known to affect
statin pharmacokinetics or myopathy risk should be taken into account
when selecting a statin and its dose for an individual patient (interacting
drugs, concomitant diseases, age, etc.). *Based on US Food and Drug
Administration–approved maximum doses; lower maximum doses may apply
in some countries.
epithelial cells, hepatocytes, and renal tubule cells and in the
endothelial cells that form the blood–brain barrier. Therefore,
ABCG2 may limit intestinal absorption and tissue penetration and enhance the renal and hepatic elimination of its substrates. One relatively common SNP, c.421C>A (p.Gln141Lys;
rs2231142), reduces the transport function of ABCG2. 27
The ABCG2 c.421C>A SNP has a frequency of ~10–15% in
Caucasians, 25–35% in Asians, and 0–5% in sub-Saharan
Africans and African Americans.27,28
Most statins are substrates of ABCG2.12,14,28 The AUC of
rosuvastatin was 144% greater, that of inactive simvastatin lactone 111% greater, and those of atorvastatin and fluvastatin 72%
greater in individuals with the ABCG2 c.421AA genotype than in
those with the c.421CC genotype (Figure 1).28,29 These increases
in plasma concentration are most likely due to increased bioavailability of the orally administered drug, as a consequence of
decreased intestinal efflux of these statins by ABCG2 in association with the c.421AA genotype. The ABCG2 genotype has no
significant effect on the pharmacokinetics of pravastatin and
pitavastatin.17,20,29 It is probable that these findings translate
into an increased risk of muscle toxicity in individuals with
the c.421AA genotype who use rosuvastatin, atorvastatin, and
fluvastatin, whereas the consequences for simvastatin therapy
are more difficult to predict. However, no studies have yet been
published on the clinical effects of ABCG2 polymorphism in the
context of statin therapy.
Other Transporters and Statins
In addition to OATP1B1 and ABCG2, many statins are also substrates of other transporters that display significant genetic variability, such as the multidrug resistance protein 1 and multidrug
resistance–associated protein 2 (MRP2) efflux transporters that
are expressed in the apical membranes of intestinal epithelial
cells, hepatocytes, and renal tubule cells.1,12,14,30 The ABCB1
(encoding multidrug resistance protein 1) haplotypes c.1236Cc.2677G-c.3435C and c.1236T-c.2677T-c.3435T have relatively
minor effects on the pharmacokinetics of atorvastatin and simvastatin acid (55–60% greater AUC in TTT/TTT individuals
132
as compared with CGC/CGC individuals) (Figure 1).31 These
ABCB1 haplotypes have no significant effect on the pharmaco­
kinetics of fluvastatin, lovastatin, pravastatin, and rosuvastatin.32 However, given that the CGC and TTT haplotypes are
relatively common (allele frequencies: 34 and 43%, respectively,
in Caucasians),31 they may play some role in the variability of
statin pharmacokinetics at the population level. A rare synonymous SNP (c.1446C>G; frequency ~1–2.5% in Caucasians) in
the ABCC2 gene, encoding MRP2, has been associated with
pravastatin pharmacokinetics.33 The AUC of pravastatin was
67% lower in individuals who are heterozygous for this SNP
than in noncarriers, probably as a consequence of increased
expression of MRP2.33 Other ABCC2 SNPs that were shown
to be associated with MRP2 expression in some studies (e.g.,
c.-24C>T, c.3563T>A, and c.4544G>A) have not been shown
to be associated with pravastatin pharmacokinetics.20,33 There
appear to be no studies on the effects of ABCC2 polymorphism
on the pharmacokinetics of other statins.
Pitavastatin and rosuvastatin are substrates of OATP1A2,3,12
an influx transporter that is expressed (among other sites) in
intestinal epithelial cells. However, it is not known whether
genetic variability in SLCO1A2 affects statin pharmacokinetics. Moreover, certain SNPs in the genes encoding the OATP2B1
(SLCO2B1), organic anion transporter 3 (SLC22A8), and bile
salt export pump (ABCB11) transporters have not shown any
association with pravastatin pharmacokinetics.7,8,20
Clinical Implications
Because the SLCO1B1 c.521T>C SNP markedly reduces the
hepatic uptake, increases the plasma concentrations of active
simvastatin acid, and enhances the risk of myopathy during
high-dose simvastatin therapy (Figure 2), it is obvious that
high-dose simvastatin therapy should be avoided in carriers of
this SNP. Given that statin-induced myopathy is a concentration-dependent adverse reaction, it is advisable to also avoid
high doses—particularly of atorvastatin and pitavastatin and
probably also of rosuvastatin and pravastatin—in carriers of this
SNP. On the basis of the currently available pharmacokinetic and
toxicity data, maximum doses can be recommended for each
genotype (Figure 3). It should be noted that, because the effects
of SLCO1B1 polymorphism differ between individual statins,
treatment alternatives exist for each genotype. Genotyping for a
single SNP can be achieved rapidly and at a low cost. SLCO1B1
genotyping should therefore be used to increase the safety of
high-dose statin therapy in clinical practice.
Analogously, ABCG2 genotyping could also be used to
guide statin therapy in clinical practice. Because ABCG2 and
OATP1B1 are not parallel systems, it is likely that their effects on
statin pharmacokinetics are additive. However, as there are currently no data related to ABCG2 polymorphism–induced clinical effects in the context of statin therapy, one may argue that
further studies are needed before any recommendation can be
made for routine genotyping of patients for the polymorphism
prior to initiating statins. This argument could be applicable to
ABCB1 genotyping as well. However, it is foreseeable that, in the
future, individualization of statin therapy will be best achieved
VOLUME 87 NUMBER 1 | january 2010 | www.nature.com/cpt
prac tice
via combined genotyping for various transporter (and other)
genes that affect the pharmacokinetics and pharmacodynamics
of statins.
Acknowledgments
The author’s work on transporter pharmacogenetics has been supported by
grants from the Helsinki University Central Hospital Research Fund (Helsinki,
Finland) and the Sigrid Jusélius Foundation (Helsinki, Finland).
Conflict of Interest
The author declared no conflict of interest.
© 2009 American Society for Clinical Pharmacology and Therapeutics
1. Neuvonen, P.J., Niemi, M. & Backman, J.T. Drug interactions with
lipid‑lowering drugs: mechanisms and clinical relevance. Clin. Pharmacol.
Ther. 80, 565–581 (2006).
2. König, J., Cui, Y., Nies, A.T. & Keppler, D. A novel human organic anion
transporting polypeptide localized to the basolateral hepatocyte
membrane. Am. J. Physiol. Gastrointest. Liver Physiol. 278, 156–164 (2000).
3. Ho, R.H. et al. Drug and bile acid transporters in rosuvastatin hepatic uptake:
function, expression, and pharmacogenetics. Gastroenterology 130,
1793–1806 (2006).
4. Tirona, R.G., Leake, B.F., Merino, G. & Kim, R.B. Polymorphisms in OATP-C:
identification of multiple allelic variants associated with altered transport
activity among European- and African-Americans. J. Biol. Chem. 276,
35669–35675 (2001).
5. Mwinyi, J., Johne, A., Bauer, S., Roots, I. & Gerloff, T. Evidence for inverse
effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics.
Clin. Pharmacol. Ther. 75, 415–421 (2004).
6. Maeda, K. et al. Effects of organic anion transporting polypeptide 1B1
haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril.
Clin. Pharmacol. Ther. 79, 427–439 (2006).
7. Nishizato, Y. et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8)
genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol.
Ther. 73, 554–565 (2003).
8. Niemi, M. et al. High plasma pravastatin concentrations are associated
with single nucleotide polymorphisms and haplotypes of organic anion
transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14,
429–440 (2004).
9. Pasanen, M.K., Neuvonen, P.J. & Niemi, M. Global analysis of genetic variation
in SLCO1B1. Pharmacogenomics 9, 19–33 (2008).
10. Kopplow, K., Letschert, K., König, J., Walter, B. & Keppler, D. Human
hepatobiliary transport of organic anions analyzed by quadruple-transfected
cells. Mol. Pharmacol. 68, 1031–1038 (2005).
11. Kameyama, Y., Yamashita, K., Kobayashi, K., Hosokawa, M. & Chiba, K.
Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5,
SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems
of HeLa and HEK293 cells. Pharmacogenet. Genomics 15, 513–522 (2005).
12. Fujino, H., Saito, T., Ogawa, S. & Kojima, J. Transporter-mediated influx and
efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase.
J. Pharm. Pharmacol. 57, 1305–1311 (2005).
13. Pasanen, M.K., Neuvonen, M., Neuvonen, P.J. & Niemi, M. SLCO1B1
polymorphism markedly affects the pharmacokinetics of simvastatin acid.
Pharmacogenet. Genomics 16, 873–879 (2006).
14. Kitamura, S., Maeda, K., Wang, Y. & Sugiyama, Y. Involvement of multiple
transporters in the hepatobiliary transport of rosuvastatin. Drug Metab.
Dispos. 36, 2014–2023 (2008).
Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 1 | january 2010
15. Deng, J.W. et al. The effect of SLCO1B1*15 on the disposition of
pravastatin and pitavastatin is substrate dependent: the contribution
of transporting activity changes by SLCO1B1*15. Pharmacogenet.
Genomics 18, 424–433 (2008).
16. Chung, J.Y. et al. Effect of OATP1B1 (SLCO1B1) variant alleles on the
pharmacokinetics of pitavastatin in healthy volunteers. Clin. Pharmacol. Ther.
78, 342–350 (2005).
17. Ieiri, I. et al. SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an
efflux transporter) variant alleles and pharmacokinetics of pitavastatin in
healthy volunteers. Clin. Pharmacol. Ther. 82, 541–547 (2007).
18. Pasanen, M.K., Fredrikson, H., Neuvonen, P.J. & Niemi, M. Different effects
of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and
rosuvastatin. Clin. Pharmacol. Ther. 82, 726–733 (2007).
19. Niemi, M., Pasanen, M.K. & Neuvonen, P.J. SLCO1B1 polymorphism
and sex affect the pharmacokinetics of pravastatin but not fluvastatin.
Clin. Pharmacol. Ther. 80, 356–366 (2006).
20. Ho, R.H. et al. Effect of drug transporter genotypes on pravastatin disposition
in European- and African-American participants. Pharmacogenet. Genomics
17, 647–656 (2007).
21. Lee, E. et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white
and Asian subjects residing in the same environment. Clin. Pharmacol. Ther.
78, 330–341 (2005).
22. Choi, J.H., Lee, M.G., Cho, J.Y., Lee, J.E., Kim, K.H. & Park, K. Influence of
OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans.
Clin. Pharmacol. Ther. 83, 251–257 (2008).
23. Kobayashi, D., Nozawa, T., Imai, K., Nezu, J., Tsuji, A. & Tamai, I. Involvement
of human organic anion transporting polypeptide OATP-B (SLC21A9) in
pH‑dependent transport across intestinal apical membrane. J. Pharmacol.
Exp. Ther. 306, 703–708 (2003).
24. Grube, M. et al. Organic anion transporting polypeptide 2B1 is a high-affinity
transporter for atorvastatin and is expressed in the human heart. Clin.
Pharmacol. Ther. 80, 607–620 (2006).
25. Igel, M. et al. Impact of the SLCO1B1 polymorphism on the pharmacokinetics
and lipid-lowering efficacy of multiple-dose pravastatin. Clin. Pharmacol. Ther.
79, 419–426 (2006).
26. Link, E. et al. SLCO1B1 variants and statin-induced myopathy—a genomewide
study. N. Engl. J. Med. 359, 789–799 (2008).
27. Robey, R.W. et al. ABCG2: a perspective. Adv. Drug Deliv. Rev. 61, 3–13 (2009).
28. Keskitalo, J.E., Zolk, O., Fromm, M.F., Kurkinen, K.J., Neuvonen, P.J. &
Niemi, M. ABCG2 polymorphism markedly affects the pharmacokinetics
of atorvastatin and rosuvastatin. Clin. Pharmacol. Ther. 86,
197–203 (2009).
29. Keskitalo, J.E., Pasanen, M.K., Neuvonen, P.J. & Niemi, M. Different
effects of the ABCG2 c.421C>A single nucleotide polymorphism on
the pharmacokinetics of fluvastatin, pravastatin, and simvastatin.
Pharmacogenomics 10, 1617–1624 (2009).
30. Chen, C. et al. Differential interaction of 3-hydroxy-3-methylglutaryl-coa
reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab. Dispos.
33, 537–546 (2005).
31. Keskitalo, J.E., Kurkinen, K.J., Neuvoneni, P.J. & Niemi, M. ABCB1
haplotypes differentially affect the pharmacokinetics of the acid and
lactone forms of simvastatin and atorvastatin. Clin. Pharmacol. Ther. 84,
457–461 (2008).
32. Keskitalo, J.E., Kurkinen, K.J., Neuvonen, M., Backman, J.T., Neuvonen, P.J. &
Niemi, M. No significant effect of ABCB1 haplotypes on the pharmacokinetics
of fluvastatin, pravastatin, lovastatin, and rosuvastatin. Br. J. Clin. Pharmacol.
68, 207–213 (2009).
33. Niemi, M. et al. Association of genetic polymorphism in ABCC2 with hepatic
multidrug resistance-associated protein 2 expression and pravastatin
pharmacokinetics. Pharmacogenet. Genomics 16, 801–808 (2006).
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