ORGANIC ANION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 67

OAT4 and RST/URAT1, located on the apical surface, are considered candidate genes
involved in efflux from the cell into the proximal tubule and/or substrate reabsorption
into the proximal tubular cell. 13 One disease thought to be a result of altered organic
anion clearance is gout. Gout can be associated with uric acid crystal deposition in
the kidney (resulting in nephropathy) or within joints (resulting in an acutely painful
inflammatory arthritis). Uric acid is a product of purine metabolism and undergoes net
reabsorption in the renal proximal tubule. URAT1, the human homolog of the gene
first identified as RST, 5 is thought to transport uric acid across the apical proximal
tubular cell. Accordingly, case-control and cohort studies have suggested that loss
of function polymorphisms on URAT1 are associated with hypouricemia . One study
found decreased renal uric acid associated with a human polymorphism close to
the N-terminus (C426T), 77 and uncovered another human polymorphism, 313A (a
deletion from 313D to 333P), that had no significant uric acid transport in Xenopus
ooyctes. 78 Nevertheless, the molecular basis of renal urate handling in vivo remains
poorly understood. A detailed understanding of molecular mechanisms underlying
uric acid clearance could result in novel pharmaceutical treatments for gout that target
uric acid transporters. 13 , 79
Competition for OAT-binding sites may explain certain types of toxic reactions.
Most of the drugs in plasma bind competitively to OATs at the level of the substrate-
binding site and influence the pharmacokinetics of other drugs. Since this transporter
system has the capacity to recognize and bind a variety of endogenous substrates,
OATs are likely to be involved in certain toxic or nephrotoxic drug reactions
(Table 4.2). 80 For example, ochratoxin A, a mycotoxin that causes Balkan nephropa-
thy, has been shown experimentally to be accumulated via OAT1 in the renal proximal
tubular cells. 35 Another example is the nephrotoxicity due to the antiviral drug

TABLE 4.2. Examples of Nephrotoxic and Neurotoxic Agents Demonstrated to Interact
with OATs
Nonsteroidal Uremic toxins Antivirals

anti-inflammatory Hippuric acid Acyclovir

drugs Indoleacetic acid Adefovir

Acetaminophen Indoxyl sulfate Azidothymidine

Diclofenac Chemotherapeutics Cidofovir

Ibuprofen Methotrexate Ganciclovir

Indomethacin Heavy Metals Mycotoxins

Ketoprofen Cadmium Ochratoxin A

Naproxen Mercury Neurotransmitter metabolites

Phenacetin Chlorinated phenoxyacetates 3,4-Dihydroxymandelic acid

Piroxicam 2,4-Dichlorophenoxyacetic 3,4-Dihydroxyphenylacetic

Salicylate acid acid (DOPAC)

Antibiotics Chlorinated haloalkenes Miscellaneous

Cephalosporins 1,2-Dichlorovinyl-L-cysteines Homovanillic acid (HVA)

Penems Hydroxyindoleacetic

acid (5-HIAA) Penicillins

Source: ref. 81.