Drug metabolism and pharmacokinetics

Inhibitory effect of zinc on the absorption of JBP485 via the gastrointestinal oligopeptide transporter (PEPT1) in rats.

PMID 21712612


The aim of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 and zinc. The plasma concentration of JBP485 after oral administration in vivo, the plasma concentration of JBP485 from the portal vein after jejunal perfusions in situ, the serosal fluid concentration of JBP485 in everted small intestine preparations and the uptake of JBP485 by HeLa-hPEPT1 cells in vitro were determined by LC-MS/MS. RT-PCR and Western blotting were used to determine the mRNA and protein levels of Pept1 in the intestinal mucosa. The AUCs of JBP485 in in vivo, in vitro and in situ studies were significantly decreased after zinc pre-administration. Kinetic analysis showed that zinc inhibits the uptake of JBP485 by decreasing the affinity of JBP485 for PEPT1 in HeLa-hPEPT1 cells. RT-PCR and Western blotting indicated that zinc had no effect on basal intestinal Pept1 expression. Our results are novel in demonstrating for the first time that zinc ions, but not zinc gluconate, can inhibit the transport activity of PEPT1. In addition, the uptake of JBP485 was not affected by changes in pH values after zinc treatment. Zinc decreases the absorption of JBP485 by inhibiting the transport activity of PEPT1; however, basal intestinal Pept1 expression does not change.