ORGANIC ANION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 64

(a) (b)

FIGURE 4.9. Knockout of organic anion transporter pairs as models for defects in renal drug
handling. ( a ) Knockout of apical organic anion transporters (OATs) might result in increased
nephrotoxicity due to “unopposed” transport of potential nephrotoxins into the proximal tubular
cell by basolateral OATs. ( b ) Conversely, knockout of basolateral OATs could lead to increased
extrarenal toxicity due to delayed clearance. (From ref. 83.)

determine whether these transport deficits translated to diminished renal secretion,
the urinary excretion of organic anions in OAT1 knockout and wild-type mice was
compared by performing clearance experiments under anesthesia. Although there was
no significant decrement in ES clearance in the OAT1 knockout mouse (as expected
given the ex vivo results above), the renal clearance of PAH was severely reduced
(Figure 4.10). Since there were no differences in glomerular filtration between the
genotypes (as determined by measurement of inulin clearance), all of this reduction
was attributable to loss of net secretion. A long body of physiological work supports
the notion that PAH is the prototype of the highly diverse set of organic anions that
are handled in common by the classical pathway. Therefore, our finding that OAT1
is responsible for the bulk of renal secretion of PAH in vivo suggests an integral
role in the functioning of this pathway, and thus in the excretion of the numerous
clinically important compounds counted among its substrates. The naturetic response
to the diuretic furosemide was also blunted in OAT1 knockout mice. Perhaps most
interesting was the accumulation of a number of endogenous metabolites in the serum
of these animals. Several of these compounds were found to inhibit PAH transport by
OAT1 in Xenopus oocytes, suggesting that they may be “true” OAT substrates in vivo.

4.6. HUMAN VARIATION AND CLINICAL IMPLICATIONS

Because the OATs are at crucial cellular interfaces for various excretory organs (such
as the liver and kidneys), variation or polymorphisms in these genes may account for
clinically important differences in drug efficacy and renal drug handling of commonly