Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Antiviral Transport

Abstract

Renal excretion is an important elimination pathway for antiviral agents, such as acyclovir (ACV), ganciclovir (GCV), and zidovudine (AZT). The purpose of this study was to elucidate the molecular mechanisms of renal ACV, GCV, and AZT transport using cells stably expressing human organic anion transporter 1 (hOAT1), hOAT2, hOAT3, and hOAT4, and human organic cation transporter 1 (hOCT1) and hOCT2. Time-and concentration-dependent uptake of ACV and GCV was observed in hOAT1-and hOCT1-expressing cells. In contrast, uptake of valacyclovir, L-valyl ester of ACV, was observed only in hOAT3-expressing cells. On the other hand, AZT uptake was observed in hOAT1-, hOAT2-, hOAT3-, and hOAT4-expressing cells. The K m values of ACV uptake by hOAT1 and hOCT1 were 342.3 and 151.2 M, respectively, whereas those of GCV uptake by hOAT1 and hOCT1 were 895.5 and 516.2 M, respectively. On the other hand, the K m values of AZT uptake by hOAT1, hOAT2, hOAT3, and hOAT4 were 45.9, 26.8, 145.1, and 151.8 M, respectively. In addition, probenecid weakly inhibited the hOAT1-mediated ACV uptake. In conclusion, these results suggest that hOAT1 and hOCT1 mediate renal ACV and GCV transport, whereas hOAT1, hOAT2, hOAT3, and hOAT4 mediate renal AZT transport. In addition, L-valyl ester appears to be important in differential substrate recognition between hOAT1 and hOAT3. hOAT1 may not be the molecule responsible for the drug interaction between ACV and probenecid.

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

“…Those include: lack of estimating toxicity of compounds that require metabolism and bioactivation by the liver, for example compounds such as acetaminophen, an analgesic with nephrotoxicity attributed to its hepatic metabolite N-acetyl-p-benzoquinone imine; lack of apical to basolateral polarity when cultured on a flat surface, which might not allow the uptake of certain antiviral drugs therefore misrepresenting its safety, for example OAT1 and OAT3, expressed at the basolateral membrane of proximal tubular epithelial cells mediating the uptake of antiviral agents tenofovir and acyclovir. 34,35 This lack of basolateral uptake of tenofovir may explain why we did not observe toxic effects in this study. Furthermore, the absence of immune or endothelial cells prevents the assessment of the nephrotoxic potential of immunologically active drugs.…”

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

“…Supporting Table 1 lists all currently known OCT1/OCT3 drug substrates. OCT1 substrates include antiviral drugs [18][19][20] and the antidiabetic drug metformin. 21 The anticancer drug oxaliplatin, 22,23 the histamine H 2 receptor antagonist cimetidine, 24,25 and the antiviral drug lamivudine 19,20 are substrates for both OCT1 and OCT3.…”

Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate

“…6 For sodium-independent uptake, organic anion-transporting polypeptides (OATPs) of the SLC21 (SLC0) family, such as OATP-B, 7,8 OATP-C, [9][10][11] and OATP8, 12,13 mediate the transport of a variety of organic anions such as sulfobromophthalein, bile salts, and sulfate-conjugated steroid hormones, although their driving forces are still unclear. In addition, organic anion transporter 2 (OAT2) in the SLC22 family mediates the transport of organic anion such as para-aminohippurate, 14 prostaglandins, 15 zidovudine, 16 tetracycline, 17 and salicylates 18 in a sodium-independent manner. Recently, Kobayashi et al 19 have reported that it also mediates the transport of steroid sulfates as well as several drugs.…”