RT Journal Article
SR Electronic
T1 Effect of 3'-azido-3'-deoxythymidine (AZT) on organic ion transport in rat renal brush border membrane vesicles.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 128
OP 133
VO 260
IS 1
A1 D A Griffiths
A1 S D Hall
A1 P P Sokol
YR 1992
UL http://jpet.aspetjournals.org/content/260/1/128.abstract
AB 3'-Azido-3'-deoxythymidine (AZT), a nucleoside analog which has potent activity against the acquired immunodeficiency virus, is actively secreted by the mammalian kidney. In order to study the mechanism of renal drug transport, the effect of AZT on the organic cation and organic anion transport systems in rat renal brush border membrane vesicles was examined by using a rapid filtration assay. The following prototypic substrates were used: [3H]N1-methylnicotinamide and [3H]tetraethylammonium for organic cations and p-[3H]aminohippurate for an organic anion. AZT inhibited pH-driven [3H]N'-methylnicotinamide transport (pHi = 6.0, pH0 = 7.5), but not as effectively as mepiperphenidol (MEPI), a known organic cation transport blocker; the corresponding IC50 values for AZT and MEPI were 2500 and 25 microM, respectively. Counterflow studies, which examined the capability of the drug to cross the plasma membrane, indicated that [3H] tetraethylammonium and MEPI trans-stimulated [3H]tetraethyl-ammonium uptake, but AZT did not. To clarify further the actions of AZT on the organic cation transporter, kinetic studies were undertaken. A Hanes-Woolf transformation of the data revealed that both AZT and MEPI inhibited [3H]N'-methylnicotinamide transport in a competitive manner. The specificity of competition was studied by looking at the effect of AZT on the organic anion transporter. Probenecid, a classical inhibitor of organic anion transport, blocked p-[3H]aminohippurate transport, but AZT did not. We conclude that AZT is a weak inhibitor of the renal brush border organic cation transport system.