POLYMORPHISMS OF DRUG TRANSPORTERS AND CLINICAL RELEVANCE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 627

transporters, 14% of the variants exhibited altered substrate specificity. Such a find-
ing will have important implications on clinical studies to investigate how SLC trans-
porter polymorphisms influence pharmacokinetic and pharmacodynamic properties
of therapeutic compounds. In general, the SLC transporter variants discussed in this
section are highlighted because of their common allele frequency and/or functional
effect.
Using a Xenopus laevis oocyte expression system, 15 nonsynonymous variants
of SLC22A1 (OCT1) were evaluated with respect to MPP + uptake. 51 Of the six
OCT1 variants with altered function, two showed reduced MPP + uptake (Arg61Cys
and Pro341Leu), three had complete loss of function (Gly220Val, Gly401Ser, and
Gly465Arg), and one variant increased accumulation of MPP + (Ser14Phe). In addi-
tion to decreased MPP + transport, the Cys88Arg, Pro341Leu, and Gly401Ser variants
have decreased transport of tetraethylammonium (TEA), and the latter two variants
have diminished ability to transport serotonin relative to the reference OCT1. 71 - 73
The Pro341Leu variant is of particular interest since it is found at a frequency of
greater than 8% in African Americans and Asian Americans. 51 Kinetic analysis of
the Arg61Cys and Pro341Leu variants with MPP + showed a simultaneous decrease
in V max and increase in K m . 51 While the relevance of V max changes measured in het-
erologous expression systems is unclear, the increased K m suggests that the Cys61
and Leu341 variants of OCT1 have decreased affinity for MPP + compared to the ref-
erence transporter. In contrast, the nonfunctional Gly465Arg OCT1 variant had im-
paired localization to the basolateral membrane relative to the reference transporter. 51
Analysis of a related transporter, OCT2, showed a reduced K m for MPP + with the
Lys432Gln variant relative to the reference transporter, suggesting increased affinity
for this substrate. 74
OATP1B1 ( SLCO1B1 ) has multiple protein-altering variants that have been func-
tionally studied in vitro and many show reduced transport of model substrates (Ta-
ble 21.1). The most common nonsynonymous polymorphisms are at residues 130
(Asn130Asp) and 174 (Val174Ala), which are located in the second extracellular
loop and fourth transmembrane domain, respectively. Asn130Asp is a common variant
(

>

30%) in African Americans, European Americans, and Japanese while Val174Ala
is common in European Americans (14%) and is much less frequent in African
Americans and Japanese ( 3%). 55 , 75 Heterologous expression of the Asn130Asp

and Val174Ala variants generally shows no effect on the transport of estrone sul-
fate and estradiol 17

<

-glucuronide. 75 - 77 Similarly, these variants had no effect on the
transport of pravastatin or the active irinotecan metabolite SN-38. 76 However, in some
systems the Val174Ala variant shows reduced uptake of both estrone sulfate and estra-
diol 17

-glucuronide. 55 , 78 A natural haplotype of these two variants ( SLCO1B1 *15)
is found in Japanese subjects at a frequency of 3%. 75 When the two variants were
expressed together, there was decreased uptake of estradiol 17 -glucuronide, estrone

3-sulfate, pravastatin, and SN-38. 76 - 78 In several studies, cellular localization experi-
ments showed that the Val174Ala variant was expressed at lower levels on the plasma
membrane and was also found in intracellular compartments. 55 , 78 It is possible that
SLCO1B1 *15 alters membrane trafficking and that the reduction in OATP1B1 trans-
porters on the plasma membrane decreases the V max . Additional nonsynonymous