Kx. Liu et al., Hydroxyprolylserine derivatives JBP923 and JBP485 exhibit the antihepatitis activities after gastrointestinal absorption in rats, J PHARM EXP, 294(2), 2000, pp. 510-515
Citations number
24
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
It has been a desire to develop orally effective therapeutic agents that re
store the liver function in chronic injury. Here we demonstrated that trans
-4-L-hydroxyprolyl-L-serine (JBP923) and cyclo-trans-4-L-hydroxyprolyl-L-se
rine (JBP485), which was previously isolated from hydrolysate of human plac
enta, exhibit potent antihepatitis activity after their oral administration
. The increase in bilirubin concentration and activities of liver cytosolic
enzymes in serum caused by alpha-naphthylisothiocyanate intoxication in ra
ts were significantly countered both after i.v. and oral administration of
these dipeptides, whereas glycyrrhizin, which has been used in the treatmen
t of chronic hepatitis, is active only after its i.v. administration. Antih
epatitis activity of dipeptides results, at least partially, from their dir
ect effect on hepatocytes because glutamic-oxaloacetic transaminase and lac
tate dehydrogenase activities in the medium of hepatotoxin-exposed primary
cultured hepatocytes were reduced by these compounds. When comparing the pl
asma concentration-time profile of JBP923 after its i.v., oral, and portal
vein injection, it is suggested that JBP923 is almost completely absorbed f
rom gastrointestinal lumen, and hepatic first-pass removal is minor. JBP923
inhibited the proton-dependent transport of glycylsarcosine in brush-borde
r membrane vesicles, suggesting that peptide transport system(s) may recogn
ize JBP923. Thus, these dipeptides are potent antihepatitis reagents that a
re still active after oral administration and may be useful for clinical ap
plications.