AJP - Renal Physiology, Vol 273, Issue 5 706-F711, Copyright © 1997 by American Physiological Society
Recognition of beta-lactam antibiotics by rat peptide transporters, PEPT1 and PEPT2, in LLC-PK1 cells
T. Terada, H. Saito, M. Mukai and K. Inui
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Japan.
PEPT1 and PEPT2 are H(+)-coupled peptide transporters expressed
preferentially in the intestine and kidney, respectively, which mediate
uphill transport of oligopeptides and peptide-like drugs such as
beta-lactam antibiotics. In the present study, we have compared the
recognition of beta-lactam antibiotics by LLC-PK1 cells stably transfected
with PEPT1 or PEPT2 cDNA. Cyclacillin (aminopenicillin) and ceftibuten
(anionic cephalosporin without an alpha-amino group) showed potent
inhibitory effects on the glycylsarcosine uptake in the PEPT1-expressing
cells. Other beta-lactams, such as cephalexin, cefadroxil, and cephradine
(aminocephalosporins), inhibited modestly the PEPT1-mediated
glycylsarcosine uptake. Except for ceftibuten, these beta-lactams showed
much more potent inhibitions on the glycylsarcosine uptake via PEPT2 than
via PEPT1. Comparison of the inhibition constant (Ki) values between
cefadroxil and cephalexin suggested that the hydroxyl group at the
NH2-terminal phenyl ring increased affinity for both PEPT1 and PEPT2. It is
concluded that PEPT2 has a much higher affinity for beta-lactam antibiotics
having an alpha-amino group than PEPT1 and that substituents at the
NH2-terminal side chain of these drugs are involved in the recognition by
both peptide transporters.
