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.
MeSH terms
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Administration, Oral
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Alanine Transaminase / blood
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Alanine Transaminase / drug effects
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Animals
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Antibodies, Monoclonal / toxicity
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Antibodies, Monoclonal, Murine-Derived
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Apoptosis / drug effects
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Caspase Inhibitors*
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Chemical and Drug Induced Liver Injury
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Disease Models, Animal
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Drug Administration Schedule
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Drug Delivery Systems
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Liver / metabolism
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Liver Diseases / drug therapy*
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Male
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Mice
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Mice, Inbred BALB C
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Pentanoic Acids / administration & dosage
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Pentanoic Acids / pharmacokinetics
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Pentanoic Acids / pharmacology*
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Tissue Distribution
Substances
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3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Murine-Derived
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Caspase Inhibitors
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Enzyme Inhibitors
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Pentanoic Acids
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anti-Fas monoclonal antibody
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Alanine Transaminase