title: Orally-administered caspase inhibitor PF-03491390 is retained in the liver for prolonged periods with low systemic exposure, exerting a hepatoprotective effect against alpha-fas-induced liver injury in a mouse model.
abstract: In a mouse model of alpha-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 alpha-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.
authors.affiliation: Discovery Biology Research, Global Research and Development, Nagoya Laboratories, Pfizer Japan, Inc., Taketoyo, Aichi, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ueno
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohmi
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Naoto
authors.initials: N
authors.lastname: Kato
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Moriguchi
authors.forename: Midori
authors.initials: M
authors.lastname: Kojima
authors.forename: Rieko
authors.initials: R
authors.lastname: Shimozono
authors.forename: Sachiko
authors.initials: S
authors.lastname: Suzuki
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Eda
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010421:Pentanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010421:Pentanoic Acids; C411023:anti-Fas monoclonal antibody; D000410:Alanine Transaminase