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

Abstract

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 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 was to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters human organic anion transporter 1 (hOAT1), human peptide transporter 1 (hPepT1), and human peptide transporter 2 (hPepT2) in detail, both as substrates and as inhibitors. Using fluorescence protein tagging and cell sorting, we established Madin-Darby canine kidney cell lines stably expressing highly functional hOAT1, hPepT1, and hPepT2. Amoxicillin and cefaclor inhibited hOAT1-mediated [ 3 H]para-aminohippuric acid uptake (K i ‫؍‬ 11.0 and 1.15 mM, respectively). However, our uptake study revealed that neither drug was transported by hOAT1. Amoxicillin and cefaclor competitively inhibited hPepT2-mediated [ 3 H]glycylsarcosine uptake (K i ‫؍‬ 733 and 65 M, respectively), whereas 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 M for cefaclor. hPepT2, and to a lesser 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.

Effects of Cranberry Juice on Pharmacokinetics of β-Lactam Antibiotics following Oral Administration

“…Figure 3A shows the mean cefaclor concentration-time curves following the concurrent administration of cefaclor and 12 oz CJC or water. The observed pharmacokinetic parameters (Table 4) were in agreement with the values in the literature (19,26). Similar to the findings with amoxicillin, we observed a significant decrease in cefaclor C max s (P Ͻ 0.01) and a slightly longer T max (P Ͼ 0.05) with the concomitant use of cranberry juice, suggesting a slower absorption rate in the presence of the juice.…”

“…hOAT3 is primarily expressed in the basolateral domain of the renal tubular epithelium. Our in vitro results suggest that these ␤-lactams may undergo active secretion as well as active reabsorption in the kidney (19).…”

“…We previously demonstrated the involvement of multiple drug transporters in the disposition of ␤-lactams (17,19). Human oligopeptide transporter 1 (hPepT1), expressed on the intestinal mucosa brush border membrane, transports both amoxicillin and cefaclor and may mediate their active intestinal absorption (19). Renal apical transporter human oligopeptide transporter 2 (hPepT2) also mediates the efficient uptake transport of both antibiotics.…”

“…There is ample evidence in the literature to suggest that carriermediated active transport plays an important role in the intestinal absorption of many ␤-lactam antibiotics (30). We previously demonstrated the involvement of multiple drug transporters in the disposition of ␤-lactams (17,19). Human oligopeptide transporter 1 (hPepT1), expressed on the intestinal mucosa brush border membrane, transports both amoxicillin and cefaclor and may mediate their active intestinal absorption (19).…”

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

“…The cDNAs encoding hOCT1 (SLC22A1) and hOCT2 (SLC22A2) were amplified from human liver and kidney mRNA by real-time polymerase chain reaction as previously described (Duan and Wang, 2010). The cDNAs encoding hOAT1 (SLC26A6) and hOAT3 (SLC26A8) were previously developed in our laboratory (Li et al, 2006). The hMATE1 (SLC47A1) plasmid was purchased from GE Dharmacon (Lafayette, CO), and the hMATE2-K plasmid was kindly provided to us by Dr. Kazuo Matsubara of Kyoto University (Kyoto, Japan) (Masuda et al, 2006).…”