Interaction of 3'-azido-3'-deoxythymidine with organic ion transport in rat renal basolateral membrane vesicles.
3'-Azido-3'-deoxythymidine (AZT), a nucleoside analog effective against the acquired immunodeficiency syndrome virus, is actively secreted by rat, rabbit and human kidney. The mechanism of AZT transport across the basolateral membrane was characterized by examining the effect of AZT on organic cation and organic anion transport systems in rat renal basolateral membrane vesicles (BLMV) by using a rapid filtration assay. The following prototypic substrates were used: N1-[3H]methylnicotinamide and [3H]tetraethylammonium (TEA) for organic cations and p-[3H]aminohippurate (PAH) for an organic anion. AZT was an effective inhibitor of PAH transport. The dose-response curves for AZT and probenecid, an organic anion inhibitor, revealed IC50 values of 225 and 15 microM, respectively. To clarify further the actions of AZT at the organic anion transporter, counterflow studies were performed. Preloading BLMV with AZT trans-stimulated the uptake of PAH. The specificity of transport was assessed by examining the effect of AZT on organic cation transport. AZT did not inhibit uptake of NMN or TEA (pHin = pHout = 7.5). However, AZT slightly inhibited uptake of TEA under optimized transport conditions (1 mM TEA load). We conclude that AZT transport in rat BLMV is mediated predominantly by the renal organic anion transport system which is consistent with the capability of an organic anion to reduce the renal clearance of AZT in vivo.
Griffiths
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DA
Department of Industrial and Physical Pharmacy, Purdue University, W. Lafayette, Indiana.
Hall
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SD
Sokol
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PP
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013757:Tetraethylammonium Compounds / Q000493:pharmacokinetics; D015215:Zidovudine / Q000493:pharmacokinetics / Q000494:pharmacology*; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
D013757:Tetraethylammonium Compounds; D009536:Niacinamide; D015215:Zidovudine; C024058:N(1)-methylnicotinamide; D010130:p-Aminohippuric Acid