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Vol. 286, Issue 2, 1037-1042, August 1998
-Lactam Antibiotics with H+/Peptide
Cotransporters in Rat Renal Brush-Border Membranes1
Department of Pharmacy, Kyoto University Hospital, Faculty of
Medicine, Kyoto University, Kyoto 606-8507, Japan
Two H+/peptide cotransporters, PEPT1 and PEPT2, are
expressed in the kidney, mediating the renal tubular reabsorption of
oligopeptides and 
-lactam antibiotics. We examined the interactions
of -lactam antibiotics with peptide transporters in rat renal
brush-border membranes by evaluating the inhibitory potencies of the
antibiotics against glycylsarcosine transport. Western blot analysis
revealed that PEPT1 and PEPT2 were expressed in the renal brush-border membranes with the apparent molecular masses of 75 and 105 kDa, respectively. Using renal brush-border membrane vesicles, the uphill
transport of glycylsarcosine was observed in the presence of an inward
H+ gradient and an inside-negative membrane potential. Two
transport systems with high affinity (Km of 50 µM) and low affinity (Km of 1.2 mM) appeared
kinetically to mediate the glycylsarcosine uptake. The inhibition
constants of the antibiotics for glycylsarcosine transport were more
closely correlated with those in stable LLC-PK1 cells
transfected with rat PEPT2 rather than PEPT1 cDNA. The -lactam antibiotics with an 
-amino group showed trans-stimulation
effects on the glycylsarcosine uptake, suggesting that these
antibiotics and glycylsarcosine share a common peptide transporter.
However, the antibiotics lacking an -amino group failed to show the
trans-stimulation effect. It is concluded that
amino--lactam antibiotics at therapeutic concentrations interact
predominantly with PEPT2 localized in the brush-border membranes of rat
kidney.
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