Integral pharmacokinetics of multiple lignan components in normal, CCl4-induced hepatic injury and hepatoprotective agents pretreated rats and correlations with hepatic injury biomarkers

• Published in: Journal of ethnopharmacology Vol. 131; no. 2; pp. 290 - 299
• Main Authors: Xie, Yuan, Hao, Haiping, Kang, An, Liang, Yan, Xie, Tong, Sun, Shiqing, Dai, Chen, Zheng, Xiao, Xie, Lin, Li, Juan, Wang, Guangji
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier 15.09.2010
• Subjects: Alanine Transaminase - blood; Animals; Area Under Curve; Aspartate Aminotransferases - blood; Biological and medical sciences; Biomarkers - blood; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - prevention & control; Cytochrome P-450 CYP3A - metabolism; Dioxoles - pharmacology; Dioxoles - therapeutic use; Disease Models, Animal; Down-Regulation; Female; Fruit; General pharmacology; Herb-Drug Interactions; Lignans - pharmacokinetics; Lignans - pharmacology; Lignans - therapeutic use; Male; Medical sciences; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phytotherapy; Plant Extracts - blood; Plant Extracts - pharmacokinetics; Plant Extracts - therapeutic use; Protective Agents - pharmacokinetics; Protective Agents - pharmacology; Protective Agents - therapeutic use; Rats; Rats, Sprague-Dawley; Reference Values; Schisandra - chemistry; Correlation; Rat; Hepatoprotector; Isozyme; Toxicity; Liver; Biological marker; Medicinal plant; CYP3A; Dicotyledones; Angiospermae; Lignan; Schisandraceae; Schisandra lignans; Digestive system; Enzyme; Pharmacognosy; Cytochrome P450; Rodentia; Integral pharmacokinetics; Liver injury; Vertebrata; Mammalia; Animal; Plant origin; Spermatophyta; Pharmacokinetics; Hepatoprotective agents
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2010.06.038

Although pharmacokinetic alternations by hepatic injury have been extensively studied, little is known about the potential influence of hepatoprotective agent's treatment. This study was aimed to investigate the holistic pharmacokinetics of multiple lignans, CYP3A regulations, and their correlations with hepatic injury biomarkers, in hepatic injured rats pretreated with or without schisandra lignan extract (SLE) and dimethyl-diphenyl-bicarboxylate (DDB). Integral pharmacokinetics of multiple lignans based on an AUC-weighting approach was determined in normal, CCl4 induced hepatic injury rats pretreated with or without SLE and DDB. Protein expression and activities of CYP3A were determined. Pharmacokinetic parameters and CYP3A activities were correlated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. CCl4 induced acute hepatic injury resulted in a nearly 8-fold enhancement of integral plasma exposures of multiple lignans, which was caused by the significant down-regulation of CYP3A. SLE and DDB pretreatment exhibited potent hepatoprotective effects, accompanied with the restored expression and activity of CYP3A, and the recovery of the respective and integral pharmacokinetics of lignans components. The integral AUC(0-tn) and CYP3A activities correlated well with ALT and AST. This study suggested that the pharmacokinetic regulating effects of hepatoprotective agent's on themselves and co-prescribed drugs should be of concern, and hepatic injury biomarkers may serve as good predictors.