title: Pharmacokinetics and mechanism of intestinal absorption of JBP485 in rats.
abstract: To investigate the pharmacokinetics and mechanism of intestinal absorption of JBP485 in rats, the pharmacokinetics of JBP485 were investigated in vivo both intravenously and orally. The effects of glycylsarcosine (Gly-Sar) on the uptake and transepithelial transport of JBP485 were examined in everted intestinal sacs, in situ jejunal perfusion, Caco-2 cells and PEPT1 transfected Hela cells. The gastrointestinal absorption of JBP485 was rapid. T(1/2β) was 2.25 ± 0.06 h, CL(plasma) was 2.99 ± 0.002 ml/min/kg, V(d) was 0.22 ± 0.05 l/kg and bioavailability was about 30% at a dosage of 25 mg/kg. JBP485 underwent rapid distribution in the tissues. Gly-Sar significantly decreased JBP485 uptake and transport in these models. A kinetic study showed that JBP485 was transported by PEPT1 in Caco-2 cells with Km and Vmax values of 0.33 ± 0.13 mM and 0.72 ± 0.06 nmol/mg protein/10 min, respectively. JBP485 appeared to have linear pharmacokinetics at intravenous doses of 6.25-100 mg/kg with minor first-pass effect, and JBP485 was mainly distributed in the kidney; JBP485 is a substrate for PEPT1 which is involved in the absorption of JBP485 in rat intestine.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.forename: Desheng
authors.initials: D
authors.lastname: Wang
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kaku
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000074011:Peptide Transporter 1; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D004151:Dipeptides; C412308:JBP 485; C412307:JBP 923; D000074011:Peptide Transporter 1; D010456:Peptides, Cyclic; C082186:SLC15A1 protein, human; D027981:Symporters; C004194:glycylsarcosine