ORGANIC ANION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 65

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PAH ES Inulin

FIGURE 4.10. Renal clearance of organic anions in wild-type and OAT1 knockout mice.
Establishment of stable plasma levels of PAH, ES, and inulin (via continuous intravenous
infusion) and then measurement of urinary excretion in wild-type mice (WT, gray bars) and
OAT1 knockout mice (KO, black bars) allowed calculation of renal clearance (ratio of rate of
urinary excretion to plasma concentration). The data represent the mean ± S.E. of measurements
in four to six mice. Renal clearance of PAH, but not of ES, was significantly lower in the
knockout mice than in the wild-type mice. Clearance of inulin, representing a measure of
glomerular filtration, was similar in wild-type and knockout mice. ∗∗∗ , p < 0 . 001. (From ref.
62.)

prescribed pharmaceuticals [e.g., ACE inhibitors, methotrexate, and nonsteroidal anti-
inflammatory drugs (NSAIDs)] as well as elimination of key metabolites. Therefore,
polymorphisms in the OAT genes may account partially for differing disease preva-
lence and risk of adverse drug reactions (ADRs) among different human subpopu-
lations. ADRs are of particular interest because there are over 2 million incidents
and approximately 100,000 deaths related to ADRs in the United States each year.
Differences in the expression or function of OATs may alter the elimination of many
pharmaceutical agents significantly, thereby increasing the risk of a significant ADR.
In particular, there has been considerable interest in single-nucleotide polymor-
phisms (SNPs) in this family of genes and their potential role in drug handling by
the kidney, thereby affecting drug concentrations and half-lives in the serum. These
considerations also apply to transport across all the barrier epithelia in which OATs
are expressed: renal clearance (OAT1, OAT2, OAT3, OAT4, and URAT1), transport
across the blood-brain barrier via the choroid plexus (OAT1 and OAT3), transport
across the placenta (OAT4), and transport across the olfactory mucosa (mouse OAT6).
It has been shown that certain coding region polymorphisms affect drug transport
by OATs. For example, certain OAT1 and OAT3 SNPs are known to affect func-
tion in Xenopus oocyte expression systems. The effects of these coding region SNPs
on in vivo drug handling remain unclear. 44 , 45 , 66 , 67 However, coding region polymor-

phisms seem relatively uncommon, 68 raising the possibility that noncoding region