DRUG TRANSPORT IN THE KIDNEY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 478

OAT4 in a competitive manner. hOAT1 exhibited the highest-affinity interactions for
thiazides, whereas hOAT3 did those for loop diuretics.

15.4.3. Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used for their
anti-inflammatory and analgesic properties. Previous studies indicated the active ac-
cumulation of NSAIDs in the renal proximal tubular cells. The accumulation of in-
domethacin and salicylate has been demonstrated in rat proximal tubular cells. 150 , 151
In particular, renal handling of salicylate was studied extensively by micropuncture
experiments in vivo, 152 isolated proximal tubules, 151 , 153 renal cortical slices, 154 , 155
and a kidney epithelial cell line. 156 In addition, there have been reports on the interac-
tion of NSAIDs with other organic anions, such as prostaglandins 157 and penicillin. 158
The results of these studies suggest that NSAIDs may be transported via the renal or-
ganic anion transport. Consistent with these results, we have previously demonstrated
the interaction of rOat1 with NSAIDs using an oocyte expression system. 159
Using S 2 -hOATs as well as S 2 -hOCT1 and S 2 -hOCT2, we elucidated the interac-
tion of human OATs and OCTs with various NSAIDs (Table 15.2). 160 NSAIDs tested
(i.e., acetaminophen, acetylsalicylate, salicylate, diclofenac, ibuprofen, indomethacin,
ketoprofen, mefenamic acid, naproxen, piroxicam, phenacetin, and sulindac) inhib-
ited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and OAT4. Although
the organic cation uptake mediated by hOCT1 and hOCT2 was also inhibited by some
NSAIDs, hOCT1 and hOCT2 did not mediate the uptake of NSAIDs. This suggests
the interactions of hOATs with NSAIDs to be associated with the pharmacokinetics
and the induction of adverse reactions of NSAIDs.

15.4.4. Antiviral Drugs
Both acyclovir (ACV) and ganciclovir (GCV) are acyclic guanosine derivatives. 161
ACV is used in the treatment of various forms of herpes simplex infections. 161 Vala-
cyclovir (VACV) is the L-valyl ester of ACV, which is active against herpes simplex
virus types 1 and 2, and varicella zoster virus. 162 GCV is used in the treatment of
cytomegalovirus infections in acquired immunodeficiency syndrome and in trans-
plant patients. 161 On the other hand, 3 -azido-3 -deoxythymidine (zidovudine, AZT)
is widely used for the treatment of HIV infection. 162 Approximately 83% of ACV, 90%
of GCV, and 80% of AZT are excreted in their unchanged forms by the kidney. 163-165
The renal excretion of ACV and AZT is reduced by probenecid, a typical inhibitor of
organic anion transport. 163 , 166 , 167 Although neither possesses a typical anionic moi-
ety, the results suggest that the renal organic anion transport system is responsible
for the tubular secretion of these drugs. On the other hand, the involvement of an or-
ganic cation transport system has also been suggested in the tubular secretion of AZT
because cimetidine, an organic cation, also reduces the renal clearance of AZT. 166
Using S 2 -hOATs as well as S 2 -hOCT1 and S 2 -hOCT2, we elucidated the interac-
tion of human OATs and OCTs with antiviral agents such as ACV, GCV, and AZT
(Table 15.2). 35 Time- and concentration-dependent uptake of ACV and GCV was