DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 480

Similar OAT-mediated drug-drug interactions have been reported for diuretics, 169 nu-
cleoside analogs, 170 and antiviral drugs. 171

15.5.2. Transporter-Mediated Nephrotoxicity
Nephrotoxic Drugs OATs are involved in the development of organ-specific toxicity
of drugs and their metabolites. For example, the nephrotoxic effects of

-lactam an-
tibiotics (e.g., cephaloridine) and carbapenem antibiotics are closely associated with
OATs, 172 and OATs are also responsible for the nephrotoxicity of antiviral drugs such
as adefovir and cidofovir. 173 -lactam antibiotics 141 and antiviral drugs 174

exhibit a significantly high cytotoxicity in OAT1-transfected cell cultures.
The nephrotoxicity of all these compounds could be reduced by coadministration
of other substrates of OATs or inhibitors of OATs. Indeed, recently, a new applica-
tion of probenecid as a nephroprotectant in therapy with the antiviral drug cidofovir
was determined. 175 When probenecid is coadministered with cidofovir, probenecid
inhibits the tubular accumulation of cidofovir, thus reducing its potential risk.

Indeed,

Environmental Substances Ochratoxin A is a mycotoxin that contaminates cereals
and is thought to be responsible for Balkan nephropathy, 176 an endemic nephropathy
that exhibits characteristic chronic tubulointerstitial changes. In OAT1-expressing
oocytes and OAT1-transfected cell cultures, the addition of ochratoxin A to the culture
media decreases cell viability. 177 This decreased cell viability is abolished by the
nontoxic substrates of OAT1, such as PAH.

Uremic Toxin The uremic toxins and their metabolites, produced during the
catabolism process within the body, seem to be associated with the exacerbation
of renal function in renal failure. Indoxyl sulfate, a uremic toxin derived from dietary
proteins, is a substrate of OATs. 178-180 Immunohistochemical analyses revealed that
5/6-nephrectomized rats, an animal model of chronic renal failure, showed higher
intensities of OAT1 and OAT3 proteins than did sham-operated rats. 180 These data
suggest that OATs are also involved in the progression of chronic renal failure. In
the body, uremic substances that cannot be eliminated by glomerular filtration during
renal failure should be removed via tubular secretion mediated by OATs. In these
cases, OAT protein expression levels increased, resulting in the accumulation of toxic
substances in the tubules. OAT1 and OAT3 are also involved in the uptake of other ure-
mic toxins, such as 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indoleacetate,
and hippurate. 181

15.5.3. In Vitro and In Vivo Model Systems to Study Renal Drug Transport

The substrate specificities of drug transporters and drug discovery based on the trans-
port mechanisms become increasingly important these days. The identification of
compounds that are accepted by transporters can help the selection and optimization
of novel drug candidates. For the screening of transport activities, high-throughput