Integral pharmacokinetics of multiple lignan components in normal, CCl4-induced hepatic injury and hepatoprotective agents pretreated rats and correlations with hepatic injury biomarkers.
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.
Xie
Yuan
Y
Key Laboratory of Drug Metabolism and Pharmacokinetics, Key Unit of SATCM for Pharmacokinetic Methodology of TCM Complex Prescription, China Pharmaceutical University, Nanjing, China.
Hao
Haiping
H
Kang
An
A
Liang
Yan
Y
Xie
Tong
T
Sun
Shiqing
S
Dai
Chen
C
Zheng
Xiao
X
Xie
Lin
L
Li
Juan
J
Wang
Guangji
G
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005638:Fruit; D041743:Herb-Drug Interactions; D017705:Lignans / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008517:Phytotherapy; D010936:Plant Extracts / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020011:Protective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D032141:Schisandra / Q000737:chemistry*
D015415:Biomarkers; D004149:Dioxoles; D017705:Lignans; D010936:Plant Extracts; D020011:Protective Agents; C041398:7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester; D002251:Carbon Tetrachloride; D051544:Cytochrome P-450 CYP3A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase