Pharmacokinetics and mechanism of intestinal absorption of JBP485 in rats.
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.
Cang
Jian
J
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
Zhang
Jian
J
Wang
Changyuan
C
Liu
Qi
Q
Meng
Qiang
Q
Wang
Desheng
D
Sugiyama
Yuichi
Y
Tsuji
Akira
A
Kaku
Taiichi
T
Liu
Kexin
K
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
D004151:Dipeptides; C412308:JBP 485; C412307:JBP 923; D000074011:Peptide Transporter 1; D010456:Peptides, Cyclic; C082186:SLC15A1 protein, human; D027981:Symporters; C004194:glycylsarcosine