Orally-Administered Caspase Inhibitor PF-03491390 Is Retained in the Liver for Prolonged Periods With Low Systemic Exposure, Exerting a Hepatoprotective Effect Against α-Fas-Induced Liver Injury in a Mouse Model

• Published in: Journal of Pharmacological Sciences Vol. 105; no. 2; pp. 201 - 205
• Main Authors: Ueno, Yoshinobu, Ohmi, Takashi, Yamamoto, Mitsuko, Kato, Naoto, Moriguchi, Yukiko, Kojima, Midori, Shimozono, Rieko, Suzuki, Sachiko, Matsuura, Tomomi, Eda, Hiroyuki
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2007; The Japanese Pharmacological Society; Elsevier
• Subjects: Administration, Oral; alanine aminotransferase (ALT); Alanine Transaminase - blood; Alanine Transaminase - drug effects; Animals; Antibodies, Monoclonal - toxicity; Apoptosis - drug effects; caspase; Caspase Inhibitors; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Administration Schedule; Drug Delivery Systems; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Fas; Liver - metabolism; Liver Diseases - drug therapy; Male; Mice; Mice, Inbred BALB C; Pentanoic Acids - administration & dosage; Pentanoic Acids - pharmacokinetics; Pentanoic Acids - pharmacology; Tissue Distribution; alanine aminotransferase (ALT); Fas; caspase
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.SC0070207

In a mouse model of α-Fas-induced acute liver injury, the orally-administered caspase inhibitor PF-03491390 (formerly named IDN-6556) was retained in the liver for prolonged periods with a low systemic exposure. Reductions in the elevated plasma levels of alanine aminotransferase (ALT) revealed that the retention of PF-03491390 in the liver exerted a hepatoprotective effect, even when pre-administered to mice 4 h before α-Fas insult. Prolonged retention of PF-03491390 in the liver after oral administration has the benefit of low systemic exposure, making this a beneficial agent for the treatment of liver diseases.