Pharmacokinetic interaction between JBP485 and cephalexin in rats.
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.
Zhang
Jian
J
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Lvshunkou District, Dalian 116044, China.
Wang
Changyuan
C
Liu
Qi
Q
Meng
Qiang
Q
Cang
Jian
J
Sun
Huijun
H
Gao
Ying
Y
Kaku
Taiichi
T
Liu
Kexin
K
D000818:Animals; D000998:Antiviral Agents / Q000097:blood* / Q000493:pharmacokinetics; D002460:Cell Line; D002478:Cells, Cultured; D002506:Cephalexin / Q000097:blood* / Q000493:pharmacokinetics; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000097:blood; D010456:Peptides, Cyclic / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D000998:Antiviral Agents; C412308:JBP 485; D027361:Organic Anion Transporters; D010456:Peptides, Cyclic; D002506:Cephalexin