Transport of Beta-Lactam Antibiotics in Kidney Brush Border Membrane: Determinants of Their Affinity for the Oligopeptide/H+ Symporter

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This study was designed to determine whether beta-lactam antibiotics (cephalosporins and penicillins) are all substrates for the renal oligopeptide/H+ symporter and, if so, whether the transport system discriminates among the numerous beta-lactam antibiotics. We used (Hydrogen-3)glycylglutamine, (Hydrogen-3)cephalexin, and (Hydrogen-3)ampicillin as probes for the transport of oligopeptides, cephalosporins, and penicillins in kidney brush border membrane vesicles, respectively. Among the beta-lactam antibiotics, only those with an alpha-amino group in the phenylacetamido moiety were found to interact with the oligopeptide/H+ symporter. Aminocephalosporins displayed high affinities (Ki s generally < 250 micromolars), whereas aminopenicillins displayed low affinities (Ki 0.78-3.03 mM). These differences in affinities appeared to be a consequence of conformational features of the substrates, especially the sterical location of the carboxy group. The affinities of aminolactams for the oligopeptide/H+ symporter were, furthermore, related to the hydrophobicity of the phenylglycyl chains and the substituents attached to the thiazolidine and dihydrothiazine ring. In sharp contrast to the uptake of (Hydrogen-3)glycylglutamine and (Hydrogen-3)cephalexin, the uptake of (Hydrogen-3)ampicillin was not dependent on a pH gradient and was inhibited by various beta-lactam antibiotics, whether or not they contained an alpha-amino group. Our data suggest that: (a) the transport of aminocephalosporins is largely mediated by the oligopeptide/H+ symporter, which is highly influenced by the substrate structure; and (b) penicillins are transported by another system, which is less discriminative with respect to substrate structure. (J. Clin. Invest. 1993. 92:2215-2223.) Key words: peptides. antibiotics. transport. kidney. brush border membrane

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