CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 783

conjugates) and uremic toxins (indoxyl sulfate, indoleacetic acid, p -hydroxyhippuric
acid, and o -hydroxyhippuric acid) has been suggested to be caused by their accu-
mulation in the renal proximal tubular cells via OATs, in particular OAT1. 547 This
hypothesis is further supported by the protective role observed for OAT inhibitors or
competitive substrates such as probenecid and several NSAIDs against nephrotoxic-
ity from ochratoxin A, adefovir, cidofovir, cephaloridine, and mercury. In this view,
drug-drug interactions due to competition for OAT transport is expected to determine
a decrease in the renal secretion, thus leading to decreased nephrotoxicity, increased
half-life, and potentially enhanced extrarenal toxicity of substrates.
For instance, ochratoxin A, a mycotoxin recently identified as an etiological fac-
tor of the endemic Balkan nephropathy, is transported by OAT1, OAT2, and OAT4.
Accumulation of ochratoxin A, in proximal tubular cells via OATs has been reported
as a primary event in the development of ochratoxin A nephrotoxicity. The OAT
inhibitor probenecid has been observed to decrease the renal clearance of ochra-
toxin A, whereas piroxicam and octanoate, which inhibit OAT1-mediated uptake
of ochratoxin A, have been reported to prevent the nephrotoxicity of ochratoxin
A. 548 - 551 Therefore, the administration of OAT inhibitors or competitive substrates
has been evaluated as a useful strategy to decrease nephrotoxicity of clinically used
nephrotoxic OAT substrate drugs such as -lactam antibiotics and antiviral nucleotide

analogs: in particular, cidofovir, adefovir, and its orally available prodrug adefovir
dipivoxil.
Organic anion transporter activity has also been proposed to be involved in the
chelation therapy of the enviromental neurotoxicant methylmercury. N -acetylcysteine
and dimercaptopropanesulfonate have been reported to increase dramatically the uri-
nary methylmercury excretions in animals and humans, probably by forming mer-
captide complexes, which are high-affinity substrates for Oat1. Therefore, organic
anion transporters may facilitate the urinary methylmercury excretion. 552 Further-
more, based on the recent detection of OAT3 at the basolateral side of the blood-
brain barrier and at the brush border membrane of the choroid plexus in rats and
mice, it has been suggested that OAT3, together with other transporters belong-
ing to the MRP family, localized at the luminal membrane of capillary endothe-
lial cells of the blood-brain barrier, may participate in the efflux of metabolites of
monoamine neurotransmitters, uremic toxins, and endogenous compounds (e.g., p -
aminohippuric acid) but also of several drugs from the brain. In particular, OAT3
and members of MRPs (especially MRP4 and MRP5) have been proposed to reduce
the brain penetration of the thiopurines nucleobase analogs 6-mercaptopurine and
6-thioguanine, drugs used widely in maintaining remission in the treatment for acute
lymphoblastic leukemia (ALL), especially in pediatric patients. It has recently been
suggested that coadministration of 6-mercaptopurine together with OAT3-specific
inhibitors could be a useful strategy to increase thiopurine concentrations in the
brain interstitial and cerebrospinal fluid, thus enhancing their pharmacological effect
to prevent CNS relapses during treatment of patients with ALL. 553 Indeed, it was
demonstrated in animal models that 6-mercaptopurine efflux from the brain was in-
hibited by OATs and/or MRPs inhibitors, such as benzylpenicillin, cimetidine, and
sulfinpyrazone. 553