RT Journal Article
SR Electronic
T1 Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Antiviral Transport
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 918
OP 924
DO 10.1124/jpet.300.3.918
VO 300
IS 3
A1 Takeda, Michio
A1 Khamdang, Suparat
A1 Narikawa, Shinichi
A1 Kimura, Hiroaki
A1 Kobayashi, Yasuna
A1 Yamamoto, Toshinori
A1 Cha, Seok Ho
A1 Sekine, Takashi
A1 Endou, Hitoshi
YR 2002
UL http://jpet.aspetjournals.org/content/300/3/918.abstract
AB 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 Kmvalues of ACV uptake by hOAT1 and hOCT1 were 342.3 and 151.2 μM, respectively, whereas those of GCV uptake by hOAT1 and hOCT1 were 895.5 and 516.2 μM, respectively. On the other hand, theKm values of AZT uptake by hOAT1, hOAT2, hOAT3, and hOAT4 were 45.9, 26.8, 145.1, and 151.8 μM, 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. The American Society for Pharmacology and Experimental Therapeutics