title: Transport of beta-lactam antibiotics in kidney brush border membrane. Determinants of their affinity for the oligopeptide/H+ symporter.
abstract: 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 [3H]glycylglutamine, [3H]cephalexin, and [3H]-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 (KiS generally < 250 microM), 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 [3H]glycylglutamine and [3H]cephalexin, the uptake of [3H]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.
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania 15213.
authors.forename: H
authors.initials: H
authors.lastname: Daniel
authors.forename: S A
authors.initials: SA
authors.lastname: Adibi
mesh_terms: D000667:Ampicillin / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000378:metabolism*; D002506:Cephalexin / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D004151:Dipeptides; D009842:Oligopeptides; D011522:Protons; C039788:glycylglutamine; D000667:Ampicillin; D002506:Cephalexin