ORGANIC ANION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 68

cidofovir (used to treat ophthalmic cytomegalovirus infection and thought to be active
against orthopox viruses such as smallpox), which is known to be mediated by active
secretion of cidofovir in the renal tubules. This effect has shown to be counteracted
by coadministration of probenecid, a potent inhibitor of organic anion secretion in
the proximal renal tubular cells. 64 Methotrexate clearance has been reported to be
reduced with NSAIDs acting as competitive substrates for the binding sites of renal
organic anion transporters. 35 The net effect of this competition is an increase in
plasma concentration of methotrexate and the manifestation of severe toxicity, in the
form of bone marrow suppression and damage to intestinal epithelium. Alternatively,
the multispecificity of OATs can be used to prolong the action of drugs by competitive
inhibition of secretion at the OAT binding site. Such inhibition decreases renal
excretion and enhances retention of drugs, an example being the common practice
of coadministering probenecid to prolong the action of

-lactam antibiotics. In sum-
mary, it may be appropriate to consider the classic secretory transporter system as a
target for the treatment of various drug-related side effects and that modification at this
cellular level could open up a new era of therapeutic strategies for clinically significant
diseases.

β

4.7. CONCLUSIONS

Since the identification of NKT (later called OAT1), OATs have been shown to play
key roles in mediating the renal absorption and excretion of drugs, xenobiotics, and
endogenous metabolites. Thus, It has become readily apparent that targeting of this
family of transporters, and an understanding of their transport mechanisms, is crit-
ical for elucidating mechanisms of drug handling and nephrotoxicity. Given that
most of the OAT family members have overlapping substrate specificities and tissue
distribution, and both primary sequence and structural homology, it would not be
that surprising if they exhibited complex, coupled regulation, as if a clustered unit.
Widespread genetic profiling of humans and a more comprehensive list of substrate
affinities may ultimately lead to individualized patient care and usher in an era where
renal drug, xenobiotic handling, and certain types of toxicity are seen in light of
OAT transport capacity. Further work will focus on the structural basis of substrate
transport as well as the creation of a list of transported endogenous and exogenous
molecules that could potentially uncover the true physiological functions of the OATs
and other SLC22 family members. Finally, the complex regulatory mechanisms likely
to underlie OAT family transcription and cell surface regulation must be understood
in vivo, and to do this, animal models, including single and multiple OAT knockouts,
must be created. These approaches should lead the field closer to a more integrated
understanding of renal drug handling and toxicity.

Acknowledgments

S.K.N. was supported by grants R01 AI057695 and HD40011, S.A.E. by DK064839.