Uptake, transport and regulation of JBP485 by PEPT1 in vitro and in vivo.
Cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) is a dipeptide with anti-hepatitis activity that has been chemically synthesized. Previous experiments in rats showed that JBP485 was well absorbed by the intestine after oral administration. The human peptide transporter (PEPT1) is expressed in the intestine and recognizes compounds such as dipeptides and tripeptides. The purposes of this study were to determine if JBP485 acted as a substrate for intestinal PEPT1, and to investigate the characteristics of JBP485 uptake and transepithelial transport by PEPT1. The uptake of JBP485 was pH dependent in human intestinal epithelial cells Caco-2. And JBP485 uptake was also significantly inhibited by glycylsarcosine (Gly-Sar, a typical substrate for PEPT1 transporters), JBP923 (a derivative of JBP485), and cephalexin (CEX, a β-lactam antibiotic and a known substrate of PEPT1) in Caco-2 cells. The rate of apical-to-basolateral transepithelial transport of JBP485 was 1.84 times higher than that for basolateral-to-apical transport. JBP485 transport was obviously inhibited by Gly-Sar, JBP923 and CEX in Caco-2 cells. The uptake of JBP485 was increased by verapamil but not by cyclosporin A (CsA) and inhibited by the presence of Zn(2+) or the toxic metabolite of ethanol, acetaldehyde (AcH) in Caco-2 cells. The in vivo uptake of JBP485 was increased by verapamil and decreased by ethanol in vivo, which was consisted with the in vitro study. PEPT1 mRNA levels were enhanced after exposure of the cells to JBP485 for 24h, compared to control. In conclusion, JBP485 was actively transported by the intestinal oligopeptide transporter PEPT1. This mechanism is likely to contribute to the rapid absorption of JBP485 by the gastrointestinal tract after oral administration.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China. liuzhihao12399@126.com
Zhihao
Z
Liu
Changyuan
C
Wang
Qi
Q
Liu
Qiang
Q
Meng
Jian
J
Cang
Lin
L
Mei
Taiichi
T
Kaku
Kexin
K
Liu
D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D017931:DNA Primers; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D000074011:Peptide Transporter 1; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
D017931:DNA Primers; C412308:JBP 485; D000074011:Peptide Transporter 1; D010456:Peptides, Cyclic; C082186:SLC15A1 protein, human; D027981:Symporters