Recognition of β-lactam antibiotics by rat peptide transporters, PEPT1 and PEPT2, in LLC-PK1 cells

Abstract

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 β-lactam antibiotics. In the present study, we have compared the recognition of β-lactam antibiotics by LLC-PK1 cells stably transfected with PEPT1 or PEPT2 cDNA. Cyclacillin (aminopenicillin) and ceftibuten (anionic cephalosporin without an α-amino group) showed potent inhibitory effects on the glycylsarcosine uptake in the PEPT1-expressing cells. Other β-lactams, such as cephalexin, cefadroxil, and cephradine (aminocephalosporins), inhibited modestly the PEPT1-mediated glycylsarcosine uptake. Except for ceftibuten, these β-lactams showed much more potent inhibitions on the glycylsarcosine uptake via PEPT2 than via PEPT1. Comparison of the inhibition constant ( K i) 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 β-lactam antibiotics having an α-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.