Biomedical Engineering Reference
In-Depth Information
TABLE 5.4. (
Continued
)
Amino Acid
In Vitro
Gene
Polymorphism
Position
Changes
Function
Refs.
5
-flanking
5
-flanking
5
-flanking
5
-flanking
5
-flanking
exon
exon
exon
exon
exon
exon
SLCO1B3
−
1590 to
−
1587 del
G-1413C
A-1345G
−
28 to
−
11 del
−
7to
−
4 del
T334G
G699A
A1272G
A1557G
G1564T
G1833A
—
—
—
—
—
S112A
M233I
L424L
A519A
G522C
G611G
?
?
?
?
?
↑
↔
↔
↔
↔↓
↔
92,93,153
SLCO2B1
A644T
C663T
T1175C
C1457T
exon
exon
exon
exon
D215V
S221S
I392T
S486F
?
?
?
68
C in codon 174, which changes an amino acid
residue located in the TM IV from valine to alanine.
38
This allele (
SLCO1B1
∗
5
) has
frequencies of approximately 15, 2, and 15% in Caucasians, African Americans, and
Asians, respectively.
38
,
68
−
72
The 388G and 521C SNPs are in linkage disequilibrium
and form the
SLCO1B1
∗
15
haplotype.
68
Pharmacokinetic studies with the HMGCo-A
reductase inhibitor pravastatin performed by different investigators strongly indicate
that people with the
SLCO1B1
∗
5
or
∗
15 genotype have increased drug exposure in
comparison to those carrying the reference allele
SLCO1B1*1a
(388A, 521T) (Ta-
ble 5.5). Presumably, differences in the bioavailability of pravastatin among peo-
ple with different
SLCO1B1
reflect the varying degrees of hepatic first-pass effect.
These findings are consistent with in vitro studies showing that the OATP1B1 521T
(V174A) variant routes poorly to the plasma membrane of expressing cells and has
decreased transport function toward a variety of substrates.
38
,
39
,
66
,
73
,
74
A few stud-
ies suggest that
SLCO1B1
∗
1b
is a high-transport-activity genotype since pravastatin
levels are lower in subjects harboring this variation than in those with the reference
allele.
70
,
75
Interestingly, in vitro studies have not observed higher transport activity of
the OATP1B1
∗
1b protein.
38
,
66
,
73
An examination of a liver bank showed a lack of in-
fluence of
SLCO1B1
genotype on the total hepatic protein expression of OATP1B1.
39
Further studies are required to clarify the mechanisms responsible for these in vivo ob-
servations. Apart from pravastatin, the pharmacokinetics of a growing number of drugs
appear to be dependent on the
SLCO1B1
521T
Another common SNP is 521T
>
C genotype, including pitavastatin,
76
rosuvastatin,
77
repaglinide,
78
nateglinide,
79
fexofenadine,
80
atrasentan,
81
valsartan,
75
irinotecan,
82
>
and ezetimibe
83
(Table 5.5). Intriguingly, there appear to be differ-
ences
in
the
impact
of
SLCO1B1
genotype
on
pravastatin
pharmacokinetics
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