Abstract
The purpose of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 (a dipeptide) and cefalexin when they were co-administered in rats. The plasma concentrations of JBP485 and cefalexin were both decreased significantly after oral combination. But little differences were observed after simultaneous intravenous administration of the two agents, suggesting that the interaction target localized in the intestine during the absorption process. The uptake in everted intestinal sacs and absorption in jejunal perfusions of JBP485 and cefalexin were dramatically reduced after drug combination. When co-administered, both the decrease in accumulative renal excretion (81.9% to 68.1% of JBP485; 91.8% to 74.5% of cefalexin) and in renal clearance (2.89 to 1.87 ml/min/kg of JBP485; 2.23 to 1.58 ml/min/kg of cefalexin) indicated that other transporter(s) are involved in the process of excretion except PEPT2. Probenecid could reduce renal excretion of JBP485 and cefalexin. Moreover, the decreased uptake of JBP485 with probenecid, PAH or PCG in kidney slices could be explained by an inhibition in kidney via OATs, at least in part. The accumulation of JBP485 in hOAT1- or hOAT3-HEK293 cells was greater than that in vector-HEK293 cells, and the uptake could be inhibited by probenecid. These findings further confirmed that the pharmacokinetic mechanism of drug-drug interaction between JBP485 and cefalexin could be explained by their inhibition of the same transporters in the intestinal mucosa (PEPT1) and kidneys (PEPT2 and OATs). We provide the first evidence that JBP485 is not only a substrate of PEPTs but also is excreted through OATs.
Footnotes
- Received January 5, 2010.
- Accepted March 10, 2010.
- The American Society for Pharmacology and Experimental Therapeutics