CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 779

major SLC22A12 renal hypouricemia allele in Japan. 501 , 503 , 504 In addition, two other
homozygous missense mutations in SLC22A12 gene, leading the substitution of thre-
onine by methionine (T217M) and glutamic acid by aspartic acid (E298D), respec-
tively, were found in subjects affected by renal hypouricaemia. 505 Very recently, a
SNP in the SLC22CA12 gene was associated with elevated serum uric acid levels
among Japanese subjects. This SNP might be an independent genetic marker for
predicting hyperuricemia, but further investigations are needed. 506
In general, OAT1 has been shown low genetic and functional diversity suggesting
its important role in body homeostasis. However, lately, 20 SNPs in human OAT1
were observed in an ethnically diverse population, of which one nonsynonymous
SNP (R50H, encoding change from arginine to histidine) was associated with in vitro
impaired transport of the nucleoside phosphonate analogs adefovir, cidofovir, and
tenofovir. 507 Analogously, in another study, only one OAT1 genetic variant (R454Q)
between six nonsynonymous SNPs identified in an ethnically diverse population was
reported to be nonfunctional, but the subsequent clinical study performed in a single
African-American family failed to demonstrate a significant difference in renal clear-
ance of the antiviral drug adefovir, a well-known OAT1 substrate, between subjects
heterozygous for the nonfunctional variant OAT1-R454Q and subjects not carrying
this variant. 508 In another study performed in a Japanese population, polymorphisms
in the OAT3 gene was not associated with changes in renal handling of the HMG-CoA
reductase inhibitor pravastatin, an expected OAT3 substrate. 509 , 510 Finally, SNPs in
the 5 regulatory regions of the SLC22A6 and SLC22A8 genes, potentially affecting
the transcription of OAT1 and OAT3, respectively, have been described, but their
importance in affecting the human variation in organic anionic drug handling as well
as the possibility of a reciprocal influence of the nucleotide polymorphisms in OAT1
and OAT3 remain to be established. 511
These studies evaluating the potential relationship between OAT SNPs and the
therapeutic effect of drugs have a significant clinical relevance. Indeed, they can help
us understand and predict altered drug responses and toxicities, in particular ethnic
subgroups that carry certain SNPs in OATs. It has been proposed that SNPs in OATs
could be responsible, in part, for the different therapeutic activity of diuretics and
ACE inhibitors, widely used antihypertensive drugs, and well-known OAT substrates.
This mechanism could at least partly explain that about two-thirds of hypertensive
patients are inadequately treated. 512 Testing for variants in OATs could also be a useful
strategy to predict a predisposition to adverse events during treatment of a large group
of the population. For instance, study of the impact of OATs SNPs on the incidence
of nephrotoxicity caused by the nucleoside phosphonate analog cidofovir (an OATs
substrate) could be clinically relevant, as cidofovir has recently been proposed for the
treatment of smallpox infections in the case of bioterrorist attacks. 512
Main Substrate Classes (Clinically Applied) and Inhibitors Generally, OATs me-
diate the transport of structurally diverse organic anions with broad overlapping sub-
strate specificities. Interspecies differences in OAT substrates have also been de-
scribed. OAT1 is an organic anion/dicarboxylate exchanger reported to transport a