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 ii-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 #l-lactam antibiotics. We used [3HIglycylglutamine, 13Hlcephalexin, and 13H1-ampicillin as probes for the transport of oligopeptides, cephalosporins, and penicillins in kidney brush border membrane vesicles, respectively. Among the lt-lactam antibiotics, only those with an a-amino group in the phenylacetamido moiety were found to interact with the oligopeptide/H+ symporter.Aminocephalosporins displayed high affinities (Kis generally < 250 ,gM), whereas aminopenicillins displayed low affinities (K; 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 13H1-glycylglutamine and I3Hlcephalexin, the uptake of 13H1-ampicillin was not dependent on a pH gradient and was inhibited by various ,-lactam antibiotics, whether or not they contained an a-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

Differential Recognition of β-Lactam Antibiotics by Intestinal and Renal Peptide Transporters, PEPT 1 and PEPT 2

“…This indicates that the dihydrothiazine ring in the cephalosporins and the thiazolidine ring in the penicillins are not differentiated to any significant extent by the renal peptide transporter. This conclusion is in contrast to the previously held notion that penicillins in general have much lower affinity than cephalosporins for the transporter (23).…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…Valacyclovir, a PEPT1 substrate and amino acid ester derivative of the active drug acyclovir, exhibits a 3-to 5-fold increase in bioavailability (Weller et al, 1993). Intestinal PEPT1 is also involved in the absorption of other peptidomimetic drug compounds and prodrugs, including b-lactam antibiotics and angiotensin converting-enzyme inhibitors (Daniel and Adibi, 1993;Ganapathy et al, 1995;Sugawara et al, 2000;Shu et al, 2001). PEPT2 is predominately expressed in renal proximal tubules and localizes to apical membranes, where it is involved in reabsorption of di-and tripeptides from the glomerular filtrate (Rubio-Aliaga et al, 2003).…”

“…Both PEPT isoforms diverge in their substrate affinity and transport capacity but share substrate specificity, transport mechanisms, and are exclusively located at apical membranes (Daniel and Adibi, 1993;Ganapathy et al, 1995;Liang et al, 1995;Leibach and Ganapathy, 1996;Saito et al, 1996;Lin et al, 1999). The mechanism Drug Transporters and NHERF PDZ Proteins for the exclusive apical localization of the PEPTs in the intestine and kidney is not clear.…”

Peptide transporter Pept1 in Cyprinus carpio L.'s intestine: cDNA cloning and sequence analysis

“…Cloning and sequence analyses of the cDNAs encoding the mammalian oligopeptide transporters [2][3][4][5][6][7] have offered insight into the molecular mechanism for the uptake of oligopeptides. They have been identified as protondependent transporters with physiological roles to absorb small peptides arising from digestion of dietary protein in the small intestine [8] and peptides generated by luminal peptidases in the kidney [9,10]. Peptide transporters belong to the SLC15 family [11].…”