Mechanism of vancomycin transport in the kidney: studies in rabbit renal brush border and basolateral membrane vesicles.
The effect of vancomycin, a putatively nephrotoxic amine glycopeptide antibiotic, on the transport of organic cations was examined in rabbit renal basolateral and brush border membrane vesicles. The studies were conducted using a rapid filtration technique and the prototypic organic cation tetraethylammonium. In basolateral membrane vesicles, vancomycin cis-inhibited the electrogenic transport of tetraethylammonium with an IC50 value of 260 microM. In contrast, gentamicin, an aminoglycoside, was without effect. Inhibition by mepiperphenidol, a classical organic cation transport inhibitor, was observed with an IC50 value of 24 microM. Countertransport, that is, trans-stimulation experiments, were initiated in order to determine whether or not vancomycin was capable of traversing the plasma membrane. Vancomycin caused trans-stimulation of tetraethylammonium uptake. The specificity of inhibition was assessed by determining the effect of vancomycin on the transport of p-aminohippurate, an organic anion. Vancomycin did not inhibit transport, whereas probenecid, a classical organic anion inhibitor, did. In the brush border membrane, vancomycin had no effect on the transport of tetraethylammonium. These data are consistent with mediated transport for vancomycin across the basolateral membrane, but not across the brush border membrane. This implies that the nephrotoxicity of vancomycin may be due to entry through the basolateral membrane and the absence of mediated egress at the brush border membrane.
Department of Medicine, Indiana University School of Medicine, Indianapolis.
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D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D001692:Biological Transport; D002412:Cations / Q000378:metabolism; D005730:Ganglionic Blockers / Q000494:pharmacology; D005839:Gentamicins / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D014640:Vancomycin / Q000493:pharmacokinetics* / Q000494:pharmacology
D002412:Cations; D005730:Ganglionic Blockers; D005839:Gentamicins; D010880:Piperidines; D014640:Vancomycin; C010482:mepiperphenidol