Pharmacokinetic Interaction between JBP485 and Cephalexin in Rats

Abstract

ABSTRACT:The purpose of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 (cyclo-trans-4-L-hydroxyprolyl-L-serine, a dipeptide) and cephalexin when they were coadministered in rats. The plasma concentrations of JBP485 and cephalexin were both decreased significantly after oral combination, but little difference was 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 cephalexin were dramatically reduced after drug combination. When JBP485 and cephalexin were coadministered, both the decrease in accumulative renal excretion (81.9-68.1% of JBP485 and 91.8-74.5% of cephalexin) and in renal clearance (2.89-1.87 ml/min/kg JBP485 and 2.23-1.58 ml/min/kg cephalexin) indicated that transporter(s) other than H ؉ / peptide transporter (PEPT) 2 are involved in the process of excretion. Probenecid could reduce renal excretion of JBP485 and cephalexin. Moreover, the decreased uptake of JBP485 with probenecid, p-aminohippuate, or benzylpenicillin in kidney slices could be explained by an inhibition in the kidney via organic anion transporters (OATs), at least in part. The accumulation of JBP485 in human (h) OAT1-or hOAT3-human embryonic kidney (HEK) 293 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 the drug-drug interaction between JBP485 and cephalexin 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.

Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics

“…The zwitterionic drugs cephalexin and cephradine are mainly transported by MATE1 (Tanihara et al ., 2007; Watanabe et al ., 2010). As they were transported by organic anion transporters OAT, but not OCT (Zhang et al ., 2010), cephalexin and cephradine are likely eliminated by tubular secretion via OAT and MATE1. Similarly, fexofenadine and the oxazolidione antibiotics N‐({(5 S )‐3‐[4‐(1,1‐dioxidothiomorpholin‐4‐yl)‐3,5‐difluorophenyl]‐2‐oxo‐1,3‐oxazolidin‐5‐yl}methyl)acetamide (PNU‐288034) were found to be substrates for MATE1 and OAT3, although they were not transported by MATE2‐K (Matsushima et al ., 2009; Lai et al ., 2010).…”

Reduced Renal Clearance of a Zwitterionic Substrate Cephalexin in Mate1-Deficient Mice

“…Aminocephalosporins such as cephalexin, however, exist as zwitterions at the physiological pH. Cephalexin was shown to be transported by OAT1 (SLC22A6), OAT3, and other anionic cepharosporins (Uwai et al, 2002;Zhang et al, 2010), but not by MRP2 (ATP-binding cassette C2) and MRP4 (Ci et al, 2007;Kato et al, 2008). Therefore, the transport mechanisms for the zwitterionic cephalosporin cephalexin in the brush-border membranes have not been fully elucidated.…”

Reduced clearance of ε-acetamidocaproic acid in rats with acute renal failure induced by uranyl nitrate

“…This result might be supported by the fact that the values for cumulative urinary excretion of EACA with probenecid were significantly smaller than the values without probenecid, as mentioned above. Similarly, the urinary excretion of EACA has been reported to be reduced by co‐administration of cimetidine, as an inhibitor of OATPs [19,28] . If this hypothesis on the OATP‐mediated renal excretion of EACA holds true, it could be speculated that the decreased Cl r of EACA in U‐ARF rats might have been partly due to the downregulation of OATPs, based on a previous study reporting a reduced expression and function of OATPs in U‐ARF rats [10–12] .…”