Received for publication August 3, 2005.
Revised December 14, 2005.
Accepted for publication January 18, 2006.

Interactions of Amoxicillin and Cefaclor with Human Renal Organic Anion and Peptide Transporters

Abstract

Amoxicillin and cefaclor are two of the widely used -lactam antibiotics in the treatment of urinary tract infections. Both drugs are eliminated mainly by the kidney and also rely on renal excretion to exert their antibacterial activities in the urinary tract. Previous studies have suggested the involvement of organic anion and oligopeptide transporters in membrane transport of -lactams. The objective of the current study is to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters hOAT1, hPepT1 and hPepT2 in detail, both as substrates and as inhibitors. Using fluorescence protein tagging and cell sorting, we established MDCK cell lines stably expressing highly functional hOAT1, hPepT1 and hPepT2. Amoxicillin and cefaclor inhibited hOAT1-mediated ³H-PAH uptake (K_i = 11.0 and 1.15 mM, respectively). However, uptake study revealed that neither drugs were transported by hOAT1. Amoxicillin and cefaclor competitively inhibited hPepT2-mediated ³H-Gly-Sar uptake (K_i = 733 µM and 65 µM, respectively), while much lower affinity for hPepT1 was observed with both antibiotics. Direct uptake studies demonstrated that amoxicillin and cefaclor were transported by hPepT1 and hPepT2. Kinetic analysis showed that hPepT2-mediated uptake of both drugs was saturable with K_m of 1.04 mM for amoxicillin and 70.2 µM for cefaclor. hPepT2, and to a less extent hPepT1, may play an important role in apical transport of amoxicillin and cefaclor in the renal tubule. hOAT1, in contrast, is not involved in basolateral uptake of these antibiotics.

Key words: antibiotics, drug transport, organic anion transport, renal transport, transporters