CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 780

wide range of organic anions but also uncharged molecules such as steroid hormones.
Typically, OAT1 substrates are compounds with a hydrophobic domain of 4 to 10 A.
In addition, functional studies suggested that substrates with an increase in the neg-
ative charge and/or with electron-attracting side groups (e.g., Cl, Br, NO 2 ) interact
with more affinity with OAT1.
OAT1 substrates include the model organic anion p -aminohippurate (PAH) and
endogenous anionic compounds such as the cyclic nucleotides cAMP and cGMP,
folate, -ketoglutarate, prostaglandin E 2 , urate, indole acetate, and indoxyl sulfate.

In addition, several classes of widely used drugs are transported by OAT1. An-
tibiotic agents (e.g.,

-lactam antibiotics—penicillins and cephalosporines, tetra-
cyclines, and quinolone gyrase inhibitors) and diuretics (e.g., furosemide, acetazo-
lamide, bumetanide, hydrochlorothiazide, ethacrynate, tienilate) are transported by
OAT1. Moreover, OAT1 substrates comprise several antiviral drugs (e.g., acyclovir,
ganciclovir, lamivudine, zidovudine, stavudine, trifluridine adefovir, cidofovir, teno-
fovir, zalcitabine), nonsteroidal anti-inflammatory drugs (NSAIDs: indomethacin,
acetylsalicylate, ketoprofen, salicylate), cimetidine, methotrexate, neurotransmitter
metabolites (e.g., vanilmandelic acid), heavy metal chelators [2,3-dimercaptopropane
sulfonate (DMPS)], test agents (fluorescein and 6-carboxyfluorescein), and toxins (in
particular, ochratoxin A) [for a review, see refs. 514 to 517]. In addition to the human
substrates, rat OAT1 has been shown to interact with several ACE inhibitors (capto-
pril, enalapril, delapril, quinapril, ramipril), angiotensin II antagonists (telmisartan,
candesartan, valsartan, losartan), the antiepileptic valproate, and several neurotrans-
mitter metabolites (e.g., 5-methoxytryptophol, 5-hydroxyindole-3-acetic acid, D,L-4-
hydroxyl-3-methoxymandelic acid). 514 - 516
Inhibitors of human OAT1 have also been reported. Probenecid, the classic in-
hibitor of the renal organic anion secretion system, has been shown to block OAT1
activity with high affinity but low specificity, as it also inhibited sat-1, OAT2, and
OAT3. Furthermore, in in vitro studies PAH cellular uptake OAT1-mediated was
inhibited by benzylpenicillin with low affinity and by cephaloridine, cephradine,
doxycycline, minocycline, oxytetracycline, and tetracycline. Human OAT1 inhibitors
include some antiviral drugs (e.g., acyclovir, adefovir, cidofovir and its prodrug, zi-
dovudine, and ganciclovir) as well as certain diuretics (furosemide, bumetanide) and
NSAIDs (diclofenac, ibuprofen, flurbiprofen, indomethacin, ketoprofen, naproxen,
etodolac, diflunisal, phenacetin, piroxicam, and salicylate). Cimetidine was shown to
inhibit OAT1 and OAT2 in a noncompetitive manner and OAT3 and OAT4 in a com-
petitive way. Pravastatin was able to block OAT1 and OAT3 activity in vitro. 514 , 517 - 521
A wider range of OAT1 inhibitors comes from in vitro experiments using the rat Oat1
isoform. In these studies several -lactam antibiotics (penicillins and cephalosporines

such as piperacillin, cloxacillin, nafcillin, cefazolin, cephalexin, cephaloridine, cef-
triaxone, cefoperazone, and others) were found to inhibit rat Oat1 activity in a com-
petitive manner as well as a wide range of clinically used antiviral drugs, diuretics
(acetazolamide, bumetanide, hydrochlorothiazide), and NSAIDs (in addition to the
compounds tested with human isoform, also salicylurate, tolmetin, benzydamine, an-
tipyrine, aminopyrine, acetylsalicylate, and paracetamol). 522 - 525 Substrate specificity
of human OAT2 has not yet been characterized completely, although based on in vitro