Vol. 294, Issue 2, 510-515, August 2000

Hydroxyprolylserine Derivatives JBP923 and JBP485 Exhibit the Antihepatitis Activities after Gastrointestinal Absorption in Rats¹

Ke-Xin Liu, Yukio Kato, Tai-Ichi Kaku, Tomofumi Santa, Kazuhiro Imai, Akira Yagi, Takashi Ishizu and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo (K.L., Y.K., T.S., K.I., Y.S.); Japan Bioproducts Industry Co. Ltd., Tomigaya, Shibuya-ku, Tokyo (T.K.); and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Gakuencho, 1, Fukuyama, Hiroshima (A.Y., T.I.), Japan

It has been a desire to develop orally effective therapeutic agents that restore the liver function in chronic injury. Here we demonstrated that trans-4-L-hydroxyprolyl-L-serine (JBP923) and cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485), which was previously isolated from hydrolysate of human placenta, exhibit potent antihepatitis activity after their oral administration. The increase in bilirubin concentration and activities of liver cytosolic enzymes in serum caused by -naphthylisothiocyanate intoxication in rats were significantly countered both after i.v. and oral administration of these dipeptides, whereas glycyrrhizin, which has been used in the treatment of chronic hepatitis, is active only after its i.v. administration. Antihepatitis activity of dipeptides results, at least partially, from their direct effect on hepatocytes because glutamic-oxaloacetic transaminase and lactate dehydrogenase activities in the medium of hepatotoxin-exposed primary cultured hepatocytes were reduced by these compounds. When comparing the plasma concentration-time profile of JBP923 after its i.v., oral, and portal vein injection, it is suggested that JBP923 is almost completely absorbed from gastrointestinal lumen, and hepatic first-pass removal is minor. JBP923 inhibited the proton-dependent transport of glycylsarcosine in brush-border membrane vesicles, suggesting that peptide transport system(s) may recognize JBP923. Thus, these dipeptides are potent antihepatitis reagents that are still active after oral administration and may be useful for clinical applications.