POLYMORPHISMS OF DRUG TRANSPORTERS AND CLINICAL RELEVANCE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 632

21.4. CLINICAL SIGNIFICANCE OF DRUG TRANSPORTER VARIANTS
All genotype-phenotype association studies require the collection or availability of
clearly defined and well-documented phenotypes. Pharmacogenetic phenotypes in-
clude drug response expressed either in a continuous (e.g., decrease in blood pressure)
or categorical (e.g., 5-year disease-free survival) manner and the presence of a drug-
related toxicity such as peripheral neuropathy, nephrotoxicity, or specific CNS distur-
bances. Appropriate phenotypes for association studies with membrane transporter
variants can be any pharmacokinetic parameter that drug transporters influence (e.g.,
CL or F) as well as measures of drug efficacy or toxicity. In the latter case, drug trans-
porters may be implicated as a major determinant of drug concentration at the target
or toxicity site. In this section we describe a number of examples of SLC and ABC
transporter polymorphisms that have been associated with clinical endpoints, ranging
from pharmacokinetics and pharmacodynamics to congenital disorders; a compre-
hensive summary of SLC and ABC transporter genotypes that have been linked to
clinical phenotypes can be found in Table 21.2.
21.4.1. SLC Transporters
Proteins in the SLC superfamily transport small molecules in a process that does not
directly utilize the energy of the cell. Most, if not all, SLC transporters have both
endogenous and xenobiotic substrates that are transported with varying degrees of
efficiency. SLC family members often have overlapping substrate specificity, although
their tissue distribution may show isoform-specific patterns. Variation in SLC genes
may cause defects in the function of physiologically important pathways such as bile
acid metabolism or autoimmune function as well as drug disposition and response.
The investigation of several serious disorders led to the discovery and characterization
of SLC gene polymorphisms.
One early example of a phenotype-genotype association study began with the
publication of a case report in 1975 in which a boy with underdeveloped musculature
and weakness as well as recurring episodes of hepatic and cerebral dysfunction was
found to have marked carnitine deficiency in skeletal muscle, plasma, and liver. 100
Oral administration of carnitine returned plasma levels to normal and symptoms
improved, although muscle and liver carnitine levels did not change. This disorder
was classified as primary systemic carnitine deficiency (SCD, OMIM 212140). 100
The pathogenic locus for SCD was mapped by linkage analysis to chromosome 5q
in a Japanese family in 1998. 101 The SLC22A5 (OCTN2) gene was cloned in 1999
and was found to transport carnitine in a sodium-dependent manner in vitro. Analysis
of three SCD family pedigrees uncovered a number of mutations that resulted in a
truncated OCTN2: a 113-bp deletion containing the start codon encoded a transporter
that lacked the first two transmembrane domains, a cytosine insertion just after the
start codon led to a frameshift, a SNP in the first codon of exon 2 resulted in the
creation of a premature stop codon, and a splice site mutation removed exon 9 and
caused a frameshift. All of these mutations abolish transporter function and cause the
carnitine deficiency phenotype. 102 At least 20 additional polymorphisms in SLC22A5