CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 785

addition, betamipron and cilastatin have been suggested to prevent nephrotoxicity of
the antimicrobial panipenem and imipenem, respectively, via inhibition of OATs. 577
Analogously, in in vitro studies, several NSAIDs (e.g., ketoprofen, diflunisal, flur-
biprofen, indomethacin, ibuprofen, naproxen, diclofenac, and diflunisal) were re-
ported to reduce significantly the cytotoxicity of adefovir and its orally available
prodrug, adefovir dipivoxil (antiviral OAT substrate drugs widely used in HIV ther-
apy and currently in clinical evaluation against chronic hepatitis B virus infections
and herpes viruses and retroviruses) at clinically relevant plasma concentrations, in-
dicating that they may exhibit in vivo nephroprotective effects when coadministered
with adefovir or other nephrotoxic OAT1 substrate drugs. 518 Moreover, the concomi-
tant administration of OAT substrate drugs and inhibitors may result in the impaired
efficacy of drugs at the renal level. Indeed, most diuretics are actively secreted by
renal OATs, thus reaching their target molecules in the kidney; coadministration of
these diuretics with inhibitors of renal organic anion transporters is predicted to re-
duce their diuretic effect. In Oat1 knockout mice a reduction in tubular secretion and
a decrease in diuretic effect of the loop diuretic furosemide was demonstrated. In
humans, after treatment with probenecid, the renal clearance of intravenously admin-
istered furosemide was decreased significantly. 570 Drug-drug interactions probably
mediated by organic anion transporters have been described between the antiviral
zidovudine (AZT) and cimetidine. In humans, cimetidine has been shown to inhibit
the renal clearance of AZT. In vitro studies have shown that AZT is an OAT1, OAT2,
OAT3, and OAT4 substrate but it is not transported by OCTs, and cimetidine has been
identified as a potent inhibitor of OAT3 (as well as OCT1 and OCT2). Thus, this
clinically relevant drug-drug interaction may be mediated by OATs. 529 , 533 , 571 , 572
In contrast, contradicting results have been reported regarding the mechanism of
interaction between the antiviral acyclovir and probenecid. In humans, after oral
administration of probenecid, the mean terminal half-life and the AUC of intra-
venously administered acyclovir were increased significantly, whereas the urinary
excretion of the antiviral drug was reduced. 573 Although probenecid showed sig-
nificant inhibition of organic anion uptake mediated by OAT1 and OAT3 in in vitro
models, it exerted only a weak inhibitory effect on the acyclovir transport mediated by
OAT1, thus suggesting that OAT1 is not responsible for the drug interaction between
acyclovir and probenecid. 529 A drug-drug interaction probably mediated by OAT3
has also been described in humans between famotidine and probenecid. Coadminis-
tration of famotidine, and probenecid resulted in increased plasma concentrations and
decreased renal clearance of famotidine, probably due to inhibition of OAT3-mediated
transport of famotidine by probenecid. 574
Finally, due to the large number of compounds that have been shown to interact
with urate transporter 1 (URAT1), modulations of URAT1 activity by drugs used clin-
ically is predicted to affect the urate plasma levels. It has been observed that several
anti-inflammatory drugs may have uricosuric or antiuricosuric effects by inhibiting or
stimulating URAT1. Drugs that stimulate the expression and the activity of URAT1
may be used in the treatment of hyperuricemia, a pathophysiological condition that
leads to problems such as gout, hypertension, and cardiovascular disease, whereas