Hydroxyprolylserine derivatives JBP923 and JBP485 exhibit the antihepatitis activities after gastrointestinal absorption in rats

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.